Variant Annotation
Available parameters and response documentation is available here
GET /lookup/chr12:25398284:C:T?add-AMP-annotation=1
{ "chromosome": "chr12", "alt": "T", "ref": "C", "pos": 25398284, "variant_id": "10190120253982840004", "regions": { "uniprot_regions": { "version": "07-Nov-2025", "items": [ { "absolute_positon": 545190166, "amino_acid": "M1-E37,D38-R97,R97-Q150,R151-M189", "chromo": "chr12", "colour": "255,0,0", "description": null, "length": 45684, "position": 25358180, "protein": "RASK_HUMAN", "type": "homo_sapiens proteome sequences", "pub_med_references": null }, { "absolute_positon": 545230251, "amino_acid": "G10-A18", "chromo": "chr12", "colour": "0,102,153", "description": "Other binding site_10-18", "length": 27, "position": 25398265, "protein": "RASK_HUMAN", "type": "binding site", "pub_med_references": null } ] }, "nih_gtex": { "version": "v10", "items": [ { "GTExJsonData": { "exon_id": "ENSG00000133703.14_3", "exon_number": "3", "expressions": { "adipose_subcutaneous": 0.24780000000000002, "adipose_visceral_omentum": 0.23040000000000002, "adrenal_gland": 0.14640000000000003, "artery_aorta": 0.16600000000000004, "artery_coronary": 0.18430000000000002, "artery_tibial": 0.2547, "bladder": 0.28900000000000003, "brain_amygdala": 0.07314000000000001, "brain_anterior_cingulate_cortex_ba24": 0.12270000000000002, "brain_caudate_basal_ganglia": 0.08968000000000002, "brain_cerebellar_hemisphere": 0.22770000000000004, "brain_cerebellum": 0.11920000000000003, "brain_cortex": 0.10820000000000002, "brain_frontal_cortex_ba9": 0.15000000000000002, "brain_hippocampus": 0.07127000000000001, "brain_hypothalamus": 0.12060000000000001, "brain_nucleus_accumbens_basal_ganglia": 0.09925000000000003, "brain_putamen_basal_ganglia": 0.05843000000000001, "brain_spinal_cord_cervical_c_1": 0.08599000000000002, "brain_substantia_nigra": 0.08305000000000001, "breast_mammary_tissue": 0.20350000000000001, "cells_cultured_fibroblasts": 0.4822, "cells_ebv_transformed_lymphocytes": 0.7015, "cervix_ectocervix": 0.20870000000000002, "cervix_endocervix": 0.1345, "colon_sigmoid": 0.19640000000000005, "colon_transverse": 0.2731, "esophagus_gastroesophageal_junction": 0.2338, "esophagus_mucosa": 0.4312, "esophagus_muscularis": 0.2765, "fallopian_tube": 0.16740000000000005, "heart_atrial_appendage": 0.11540000000000002, "heart_left_ventricle": 0.07880000000000001, "kidney_cortex": 0.11110000000000002, "kidney_medulla": 0.13740000000000002, "liver": 0.0748, "lung": 0.2681, "minor_salivary_gland": 0.2847, "muscle_skeletal": 0.1267, "nerve_tibial": 0.2916, "ovary": 0.11820000000000003, "pancreas": 0.1048, "pituitary": 0.08331000000000001, "prostate": 0.12090000000000001, "skin_not_sun_exposed_suprapubic": 0.21860000000000002, "skin_sun_exposed_lower_leg": 0.2436, "small_intestine_terminal_ileum": 0.24810000000000001, "spleen": 0.12360000000000002, "stomach": 0.21800000000000003, "testis": 0.23240000000000002, "thyroid": 0.16120000000000004, "uterus": 0.15950000000000003, "vagina": 0.2431, "whole_blood": 0.2826 }, "gencode_id": "ENSG00000133703", "gene": "KRAS", "gene_model_positions": { "chromosome": "chr12", "end": 25403870, "start": 25358180, "strand": "-" }, "gene_positions": { "chromosome": "chr12", "end": 25403870, "start": 25358180, "strand": "-" } }, "absolute_positon": 545230195, "chromo": "chr12", "length": 121, "position": 25398209 } ] } }, "variant_type": "SNV", "cytobands": "12p12.1", "refseq_transcripts": [ { "items": [ { "name": "NM_004985.5", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.35G>A", "hgvs_p1": "G12D", "hgvs_p3": "p.(Gly12Asp)", "location": "exon 2 of 5 position 46 of 122", "coding_location": "12 of 189", "canonical": true, "gene_symbol": "KRAS", "splice_distance": "46", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": "ENST00000311936.8", "mane_plus": null, "uniprot_id": null }, { "name": "NM_033360.4", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.35G>A", "hgvs_p1": "G12D", "hgvs_p3": "p.(Gly12Asp)", "location": "exon 2 of 6 position 46 of 122", "coding_location": "12 of 190", "canonical": false, "gene_symbol": "KRAS", "splice_distance": "46", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": "ENST00000256078.10", "uniprot_id": null }, { "name": "NM_001369786.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.35G>A", "hgvs_p1": "G12D", "hgvs_p3": "p.(Gly12Asp)", "location": "exon 2 of 6 position 46 of 122", "coding_location": "12 of 190", "canonical": false, "gene_symbol": "KRAS", "splice_distance": "46", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001369787.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.35G>A", "hgvs_p1": "G12D", "hgvs_p3": "p.(Gly12Asp)", "location": "exon 2 of 5 position 46 of 122", "coding_location": "12 of 189", "canonical": false, "gene_symbol": "KRAS", "splice_distance": "46", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null } ], "version": "232" } ], "ensembl_transcripts": [ { "items": [ { "name": "ENST00000256078.4", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.35G>A", "hgvs_p1": "G12D", "hgvs_p3": "p.(Gly12Asp)", "location": "exon 2 of 6 position 46 of 122", "coding_location": "12 of 190", "canonical": true, "gene_symbol": "KRAS", "splice_distance": "46", "ensembl_support_level": "1", "ensembl_appris": "alternative1", "mane_select": null, "mane_plus": "NM_033360.4", "uniprot_id": "P01116" }, { "name": "ENST00000311936.3", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.35G>A", "hgvs_p1": "G12D", "hgvs_p3": "p.(Gly12Asp)", "location": "exon 2 of 5 position 46 of 122", "coding_location": "12 of 189", "canonical": false, "gene_symbol": "KRAS", "splice_distance": "46", "ensembl_support_level": "1", "ensembl_appris": "principal4", "mane_select": "NM_004985.5", "mane_plus": null, "uniprot_id": "P01116" }, { "name": "ENST00000556131.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.35G>A", "hgvs_p1": "G12D", "hgvs_p3": "p.(Gly12Asp)", "location": "exon 2 of 3 position 46 of 122", "coding_location": "12 of 44", "canonical": false, "gene_symbol": "KRAS", "splice_distance": "46", "ensembl_support_level": "1", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000557334.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.35G>A", "hgvs_p1": "G12D", "hgvs_p3": "p.(Gly12Asp)", "location": "exon 2 of 3 position 46 of 122", "coding_location": "12 of 76", "canonical": false, "gene_symbol": "KRAS", "splice_distance": "46", "ensembl_support_level": "5", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null } ], "version": "115" } ], "gnomad_exomes": [ { "version": "2.1.1", "filter": "PASS", "ac": 1, "an": 249328, "af": 4.010780979272284e-6, "ac_nfe": 1, "ac_nfe_nwe": 1, "ac_nfe_female": 1, "ac_female": 1, "an_afr": 16052, "an_amr": 34444, "an_asj": 9964, "an_eas": 18350, "an_eas_kor": 3816, "an_eas_jpn": 152, "an_eas_oea": 14382, "an_fin": 21608, "an_nfe": 112572, "an_nfe_bgr": 2664, "an_nfe_est": 242, "an_nfe_nwe": 42080, "an_nfe_onf": 30698, "an_nfe_seu": 11380, "an_nfe_swe": 25508, "an_oth": 6098, "an_sas": 30240, "an_afr_male": 6096, "an_amr_male": 14270, "an_asj_male": 5130, "an_eas_male": 9042, "an_fin_male": 11256, "an_nfe_male": 62984, "an_oth_male": 3190, "an_sas_male": 22754, "an_afr_female": 9956, "an_amr_female": 20174, "an_asj_female": 4834, "an_eas_female": 9308, "an_fin_female": 10352, "an_nfe_female": 49588, "an_oth_female": 2908, "an_sas_female": 7486, "an_male": 134722, "an_female": 114606, "age_hist_het_65_70": 1, "variant_type": "multi-snv", "main_data": "ƒ = 0.00000401" } ], "gnomad_exomes_coverage": [ { "version": "2.1", "coverage_mean": [ 59.50400161743164 ], "coverage_median": [ 61.0 ], "coverage_20_frequency": [ 0.8506424146244698 ] } ], "gnomad_genomes_coverage": [ { "version": "2.1", "coverage_mean": [ 31.334999084472656 ], "coverage_median": [ 31.0 ], "coverage_20_frequency": [ 0.9536118655964843 ] } ], "dann_snvs": [ { "version": "2014", "dann_score": 0.9977568895535142 } ], "ncbi_clinvar2": [ { "version": "07-Dec-2025", "review_status": "criteria provided, multiple submitters, no conflicts", "review_stars": 2, "variation_id": 12582, "num_submitters": 27, "pub_med_references": [ 1875403, 7773929, 8439212, 12720172, 15093544, 15696205, 15842656, 16474405, 17332249, 17704260, 17910045, 19047918, 19358724, 20805368, 20949522, 21079152, 22499344, 22683711, 23096712, 23174937, 23255105, 24629489, 25623042, 25695684, 26242988, 26521233, 26861459, 29298116, 30443000, 30544177, 30902772, 30936194, 31836588, 31891627, 34114335, 35794233 ], "clinical_significance": [ "Likely Pathogenic", "Pathogenic" ], "last_evaluation": "20251201", "origin": null, "accessions": [ { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Linear nevus sebaceous syndrome", "submissions": [ { "submitter_date": 20250702, "submission_description": [ "Detected variant allele frequency: 2%. The following ACMG criteria has been used: PS2_su, PS3_su, PM1_m, PP2_su, PP3_m" ], "review_description": "Likely pathogenic", "submitter_name": "Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet", "review_date": 20250430, "diseases": [ { "symbols": { "omim": "163200" } } ], "method": "clinical testing", "date_updated": 20250816, "origin": "germline", "clinical_significance": [ "Likely pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV006304919" }, { "submitter_date": 20220309, "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20120610, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_disease": [ "Linear Nevus Sebaceous Syndrome" ], "normalized_cancer": [ "SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC" ], "names": [ "Linear Nevus Sebaceous Syndrome" ] } ], "method": "literature only", "date_updated": 20220312, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000051861" }, { "submitter_name": "Equipe Genetique des Anomalies du Developpement, Université de Bourgogne", "submitter_date": 20210614, "submission_description": [], "review_description": "Pathogenic", "diseases": [ { "symbols": { "omim": "163200" } } ], "method": "clinical testing", "date_updated": 20210619, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001736991" } ], "submission_description": [], "review_date": 20250430, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_disease": [ "Linear Nevus Sebaceous Syndrome" ], "normalized_cancer": [ "SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC" ], "symbols": { "orphanet": "2612", "omim": "163200", "medgen": "C4552097", "mondo": "MONDO:0008097", "human_phenotype_ontology": "HP:0010817" }, "names": [ "Linear Nevus Sebaceous Syndrome", "Jadassohn Nevus Phakomatosis", "Linear Nevus Sebaceous Syndrome", "Organoid Nevus Phakomatosis", "Sfm Syndrome", "Linear Nevus Sebaceous Syndrome", "Sebaceous Nevus Syndrome Hemimegalencephaly", "Linear Nevus Sebaceous Syndrome", "Linear Nevus Sebaceous Syndrome", "Linear Sebaceous Nevus Sequence" ] } ], "date_created": 20130404, "clinical_significance": [ "Pathogenic", "Likely pathogenic" ], "review_description": "Pathogenic/Likely pathogenic", "allele_id": 27621, "accession_id": "RCV000029215" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND RASopathy", "submissions": [ { "submitter_date": 20250213, "submission_description": [ "This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 12 of the KRAS protein (p.Gly12Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported in the literature as a somatic event (present in tissue from a lesion but not in non-lesional tissue or peripheral blood) in individuals with congenital cutaneous disorders (PMID: 20805368, 22683711, 23096712, 23255105, 26521233). KRAS p.Gly12Asp is a frequently occurring somatic variant in several different types of cancers, including lung, ovarian, endometrial and pancreatic (PMID: 26861459, 1875403, 24629489, 23174937). ClinVar contains an entry for this variant (Variation ID: 12582). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 15093544, 25623042). For these reasons, this variant has been classified as Pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Labcorp Genetics (formerly Invitae), Labcorp", "review_date": 20241007, "diseases": [ { "symbols": { "medgen": "CN166718" } } ], "method": "clinical testing", "date_updated": 20250304, "origin": "germline", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000659085" }, { "submitter_date": 20221110, "submission_description": [ "Variant summary: KRAS c.35G>A (p.Gly12Asp) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249328 control chromosomes (gnomAD). c.35G>A is a well classified pathogenic somatic mutation (ClinVar ID 2582). c.35G>A has been reported with varying levels of somatic mosaicism in individuals affected with anomalous pancreaticobiliary ductal union, epidermal nevus and Keratinocytic epidermal nevi and Schimmelpenning syndrome characterized by nevus sebaceous and extracutaneous abnormalities (Examples: Shimotake_2003, Bourdeaut_2010 and Hafner_2012, Groesser_2012). Experimental evidence have demonstrated that KRAS G12D is embryonically lethal in the mouse model and conditional expression in mouse embryonic fibroblasts causes enhanced proliferation and partial transformation consistent with a gain of function mechanism of disease (example: Tuveson_2004). A different variant affecting the same residue G12S is associated with Cardio-facio-cutaneous syndrome in HGMD (Nava_2007). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Women's Health and Genetics/Laboratory Corporation of America, LabCorp", "review_date": 20221005, "diseases": [ { "symbols": { "medgen": "CN166718" } } ], "method": "clinical testing", "date_updated": 20221119, "origin": "germline", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002601600" } ], "submission_description": [], "review_date": 20241007, "diseases": [ { "normalized_disease": [ "Rasopathy" ], "symbols": { "medgen": "C5555857", "mondo": "MONDO:0021060" }, "names": [ "Rasopathy", "Rasopathies", "Noonan Spectrum Disorder" ] } ], "date_created": 20171226, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000548006" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND multiple conditions", "submissions": [ { "submitter_date": 20241220, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Fulgent Genetics, Fulgent Genetics", "review_date": 20240223, "diseases": [ { "symbols": { "omim": "108010" } }, { "symbols": { "omim": "109800" } }, { "symbols": { "omim": "114480" } }, { "symbols": { "omim": "163200" } }, { "symbols": { "omim": "211980" } }, { "symbols": { "omim": "260350" } }, { "symbols": { "omim": "600268" } }, { "symbols": { "omim": "601626" } }, { "symbols": { "omim": "609942" } }, { "symbols": { "omim": "613659" } }, { "symbols": { "omim": "614470" } }, { "symbols": { "omim": "615278" } } ], "method": "clinical testing", "date_updated": 20250125, "origin": "germline", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005634967" } ], "submission_description": [], "review_date": 20240223, "diseases": [ { "pub_med": [ 15604628, 18163131, 17508274, 24366376, 24366402, 24432435, 26389210, 26389258, 34242744, 31429903 ], "normalized_cancer": [ "Breast" ], "symbols": { "omim": "114480", "medgen": "C0346153", "mondo": "MONDO:0016419" }, "names": [ "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma" ], "normalized_disease": [ "Hereditary Breast Carcinoma" ], "keyword": "Hereditary cancer syndrome", "disease_mechanism": "loss of function" }, { "pub_med": [ 20876176 ], "normalized_disease": [ "Noonan Syndrome 3" ], "symbols": { "orphanet": "648", "omim": "609942", "medgen": "C1860991", "mondo": "MONDO:0012371" }, "names": [ "Noonan Syndrome 3" ] }, { "normalized_disease": [ "Linear Nevus Sebaceous Syndrome" ], "normalized_cancer": [ "SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC" ], "symbols": { "orphanet": "2612", "omim": "163200", "medgen": "C4552097", "mondo": "MONDO:0008097", "human_phenotype_ontology": "HP:0010817" }, "names": [ "Linear Nevus Sebaceous Syndrome", "Jadassohn Nevus Phakomatosis", "Linear Nevus Sebaceous Syndrome", "Organoid Nevus Phakomatosis", "Sfm Syndrome", "Linear Nevus Sebaceous Syndrome", "Sebaceous Nevus Syndrome Hemimegalencephaly", "Linear Nevus Sebaceous Syndrome", "Linear Nevus Sebaceous Syndrome", "Linear Sebaceous Nevus Sequence" ] }, { "normalized_disease": [ "Toriello-Lacassie-Droste Syndrome" ], "symbols": { "orphanet": "3339", "omim": "600268", "medgen": "C1838329", "mondo": "MONDO:0010854" }, "names": [ "Toriello-Lacassie-Droste Syndrome" ] }, { "normalized_disease": [ "Arteriovenous Malformations of the Brain" ], "symbols": { "orphanet": "46724", "omim": "108010", "medgen": "C0917804", "mondo": "MONDO:0007154", "human_phenotype_ontology": "HP:0002408" }, "names": [ "Arteriovenous Malformations of the Brain", "Cerebral Arteriovenous Malformations", "Arteriovenous Malformations of the Brain" ] }, { "normalized_cancer": [ "Malignant Tumor", "Bladder/Urinary Tract" ], "symbols": { "omim": "109800", "medgen": "C0005684", "mondo": "MONDO:0001187" }, "names": [ "Urinary Bladder Cancer", "Urinary Bladder Cancer", "Urinary Bladder Neoplasm", "Childhood Bladder Carcinoma" ], "normalized_disease": [ "Urinary Bladder Cancer", "Urinary Bladder Neoplasm", "Childhood Bladder Carcinoma" ], "keyword": "Hereditary cancer syndrome" }, { "normalized_disease": [ "Autoimmune Lymphoproliferative Syndrome Type 4" ], "symbols": { "orphanet": "268114", "omim": "614470", "medgen": "C2674723", "mondo": "MONDO:0013767" }, "names": [ "Autoimmune Lymphoproliferative Syndrome Type 4", "Autoimmune Lymphoproliferative Syndrome Type 4", "Autoimmune Lymphoproliferative Syndrome Type 4" ] }, { "pub_med": [ 22138009, 23970018, 32171751 ], "normalized_disease": [ "Acute Myeloid Leukemia" ], "normalized_cancer": [ "Acute Myeloid Leukemia", "Acute non-lymphocytic leukemia", "Acute granulocytic leukemia", "Leukemia, acute myelogenous, somatic" ], "symbols": { "omim": "601626", "medgen": "C0023467", "orphanet": "519", "mesh": "D015470", "mondo": "MONDO:0018874", "human_phenotype_ontology": "HP:0006728" }, "names": [ "Acute Myeloid Leukemia", "Acute Myeloid Leukemia, Adult", "Aml Adult", "Acute Myeloid Leukemia", "Acute Myeloid Leukemia", "Acute Myeloid Leukemia", "Leukemia, Acute Myelogenous, Somatic" ], "disease_mechanism": "Constitutively activated FLT3" }, { "normalized_disease": [ "Cardiofaciocutaneous Syndrome 2" ], "symbols": { "orphanet": "1340", "omim": "615278", "medgen": "C3809005", "mondo": "MONDO:0014112" }, "names": [ "Cardiofaciocutaneous Syndrome 2" ] }, { "pub_med": [ 25645574 ], "normalized_cancer": [ "Pancreas" ], "symbols": { "omim": "260350", "medgen": "C2931038", "mondo": "MONDO:0015278" }, "names": [ "Familial Pancreatic Carcinoma" ], "normalized_disease": [ "Familial Pancreatic Carcinoma" ], "keyword": "Hereditary cancer syndrome" }, { "normalized_disease": [ "Gastric Cancer" ], "normalized_cancer": [ "Esophagus/Stomach", "Malignant Tumor" ], "symbols": { "omim": "613659", "medgen": "C0024623", "mesh": "D013274", "mondo": "MONDO:0001056", "human_phenotype_ontology": "HP:0012126" }, "names": [ "Gastric Cancer", "Gastric Cancer", "Gastric Cancer" ] }, { "pub_med": [ 29398453 ], "normalized_disease": [ "Lung Cancer" ], "normalized_cancer": [ "Lung", "Malignant Tumor" ], "symbols": { "omim": "211980", "medgen": "C0242379", "mondo": "MONDO:0008903" }, "names": [ "Lung Cancer", "Lung Cancer", "Lung Cancer" ] } ], "date_created": 20250125, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV005007840" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Autoimmune lymphoproliferative syndrome type 4", "submissions": [ { "submitter_date": 20250526, "submission_description": [ "The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012582 /3billion dataset / PMID: 21079152). Different missense changes at the same codon (p.Gly12Ala, p.Gly12Arg, p.Gly12Cys, p.Gly12Ser, p.Gly12Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012578, VCV000012579, VCV000012583, VCV000012584, VCV000045122, VCV001701193 /PMID: 17704260). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline." ], "review_description": "Pathogenic", "submitter_name": "3billion", "review_date": 20240105, "diseases": [ { "symbols": { "omim": "614470" } } ], "method": "clinical testing", "date_updated": 20250629, "origin": "germline", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002318898" }, { "submitter_date": 20220309, "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20120610, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_cancer": [ "RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC" ], "names": [ "Ras-Associated Autoimmune Leukoproliferative Disorder, Somatic" ] } ], "method": "literature only", "date_updated": 20220312, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000191997" } ], "submission_description": [], "review_date": 20240105, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_disease": [ "Autoimmune Lymphoproliferative Syndrome Type 4" ], "symbols": { "orphanet": "268114", "omim": "614470", "medgen": "C2674723", "mondo": "MONDO:0013767" }, "names": [ "Autoimmune Lymphoproliferative Syndrome Type 4", "Autoimmune Lymphoproliferative Syndrome Type 4", "Autoimmune Lymphoproliferative Syndrome Type 4" ] } ], "date_created": 20141122, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000144970" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND not provided", "submissions": [ { "submitter_date": 20241108, "submission_description": [ "PP3, PM2, PS3, PS4" ], "review_description": "Pathogenic", "submitter_name": "Mayo Clinic Laboratories, Mayo Clinic", "review_date": 20231103, "diseases": [ { "names": [ "Not Provided" ] } ], "method": "clinical testing", "date_updated": 20241124, "origin": "germline", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005414064" }, { "submitter_date": 20221228, "submission_description": [ "Reported as a somatic variant in affected tissue from individuals with sebaceous nevi; the variant was not detected in blood or unaffected skin tissue of these individuals (Groesser et al., 2012; Levinsohn et al., 2013; Wang et al., 2015); Observed as a presumably somatic variant associated with malignancies, including various types of leukemia (Paulsson et al., 2008; Koorstra et al., 2008; Tyner et al., 2009; Zhang et al., 2011); Published functional studies demonstrate this variant affects GTP binding activity of the KRAS protein (Chen et al., 2013), and causes an increase in AKT phosphorylation (Petrova et al., 2016); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18813118, 23096712, 23437064, 24803665, 15093544, 19847165, 22264792, 21451123, 21502497, 18308936, 11323676, 26521233, 20805368, 19075190, 21680795, 30394973, 30936194, 30355600, 31836588, 29298116, 32246016, 30443000, 31891627, 33244099, 22683711, 27362559, 17875937, 29493581, 17910045)" ], "review_description": "Pathogenic", "submitter_name": "GeneDx", "review_date": 20221222, "diseases": [ { "names": [ "Not Provided" ] } ], "method": "clinical testing", "date_updated": 20221231, "origin": "germline", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000329383" }, { "submitter_date": 20251002, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "CeGaT Center for Human Genetics Tuebingen", "review_date": 20221201, "diseases": [ { "symbols": { "medgen": "CN517202" } } ], "method": "clinical testing", "date_updated": 20251025, "origin": "germline", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002821689" }, { "submitter_date": 20220516, "submission_description": [ "This is a recurrent pathogenic variant that has previously been reported in several individuals with sporadic brain arteriovenous malformations (PMID: 29298116, 30902772, 30544177). The c.35G>A variant substitutes the glycine at codon 12 with aspartic acid. Experimental studies suggest that codon 12 substitutions lead to hyperactivation of the KRAS protein (PMID: 29298116)." ], "review_description": "Pathogenic", "submitter_name": "Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital", "review_date": 20210813, "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20220611, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002525678" }, { "submitter_name": "Department of Pathology and Laboratory Medicine, Sinai Health System", "submitter_date": 20221122, "submission_description": [], "review_description": "Pathogenic", "diseases": [ { "names": [ "Not Provided" ] } ], "method": "clinical testing", "date_updated": 20221129, "origin": "unknown", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001550138" } ], "submission_description": [], "review_date": 20231103, "diseases": [ { "symbols": { "medgen": "C3661900" }, "names": [ "Not Provided", "None Provided" ] } ], "date_created": 20161206, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000272938" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Cerebral arteriovenous malformation", "submissions": [ { "submitter_date": 20231212, "submission_description": [ "The KRAS c.35G>A (p.Gly12Asp) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with vascular malformations including numerous individuals with brain arteriovenous malformations (Nikolaev SI et al., PMID: 29298116; Lihua J et al., PMID: 29381910; Al-Olabi et al., PMID: 29461977; Goss JA et al., PMID: 31486960; Schmidt FV et al., PMID: 34114335; Mitchell BJ et al., PMID: 30394973). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic variant in both a somatic and germline state by multiple submitters (ClinVar ID: 12582) and in numerous cancer cases as a somatic variant in the cancer database COSMIC (COMIC ID: COSV55497369). This variant is only observed on 2/152,128 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. The KRAS c.35G>A (p.Gly12Asp) variant resides within the P-loop region of KRAS that is defined as a critical functional domain (Gelb BD et al., PMID: 29493581). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KRAS function. In support of this prediction, functional studies show that this variant activates mitogen-activated protein kinase kinase 1 signaling pathway, leading to the formation of vascular malformation (Cistea IC et al., PMID: 23059812; Fish JE et al., PMID: 32552404; Janardhan HP et al., PMID: 32405640). The KRAS gene is defined by the ClinGen's RASopathies expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Gelb BD et al., PMID: 29493581). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the KRAS c.35G>A (p.Gly12Asp) variant is classified as pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Clinical Genomics Laboratory, Washington University in St. Louis", "review_date": 20231103, "diseases": [ { "symbols": { "omim": "108010" } } ], "method": "clinical testing", "date_updated": 20231224, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV004176950" }, { "submitter_date": 20180306, "submission_description": [ "Using exome DNA sequencing and droplet digital PCR analysis, Nikolaev et al. (2018) identified a gly12-to-asp (G12D, c.35G-A) mutation in a total of 32 of 72 arteriovenous malformations of the brain (BAVM; 108010), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12V variant (190070.0026) were present in 2.4 to 4.0% of the sequence reads per sample. The G12D mutation drove MAPK-ERK activity in endothelial cells." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20180306, "pub_med_references": [ 29298116 ], "diseases": [ { "normalized_disease": [ "Arteriovenous Malformations of the Brain" ], "normalized_cancer": [ "CNS/Brain" ], "names": [ "Arteriovenous Malformations of the Brain" ] } ], "method": "literature only", "date_updated": 20180314, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000693723" }, { "submitter_name": "Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School", "submitter_date": 20190905, "submission_description": [], "review_description": "Pathogenic", "diseases": [ { "symbols": { "omim": "108010" } } ], "date_updated": 20250413, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000992585" } ], "submission_description": [], "review_date": 20231103, "pub_med_references": [ 29298116 ], "diseases": [ { "normalized_disease": [ "Arteriovenous Malformations of the Brain" ], "symbols": { "orphanet": "46724", "omim": "108010", "medgen": "C0917804", "mondo": "MONDO:0007154", "human_phenotype_ontology": "HP:0002408" }, "names": [ "Arteriovenous Malformations of the Brain", "Cerebral Arteriovenous Malformations", "Arteriovenous Malformations of the Brain" ] } ], "date_created": 20180314, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000585796" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Cardiovascular phenotype", "submissions": [ { "submitter_date": 20240424, "submission_description": [ "reported for somatic cases only, for germline findings, please reassess" ], "review_description": "Likely pathogenic", "submitter_name": "Ambry Genetics", "review_date": 20220822, "finding": [ { "symbols": { "medgen": "CN230736" } } ], "method": "clinical testing", "date_updated": 20240501, "origin": "germline", "clinical_significance": [ "Likely pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005023563" } ], "submission_description": [], "review_date": 20220822, "diseases": [ { "symbols": { "medgen": "CN230736" }, "names": [ "Cardiovascular Phenotype" ] } ], "date_created": 20240501, "clinical_significance": [ "Likely pathogenic" ], "review_description": "Likely pathogenic", "allele_id": 27621, "accession_id": "RCV004018620" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Congenital Pulmonary Airway Malformations", "submissions": [ { "submitter_date": 20240515, "submission_description": [ "The c.35G>A variant in KRAS is an established pathogenic variant almost always exclusively found in tissue analysis of individuals with somatic cancers or tissue-limited phenotypes, and it has been deposited in ClinVar [ClinVar ID: 12582] as Pathogenic. The c.35G>A variant is observed in 5 alleles with 0 homozygote in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), which might be due to clonal hematopoesis of indeterminate potential or emerging/existing hematologic malignancies in variant carrying individuals in those databases. The c.35G>A variant in KRAS is located in exon 2 of this 5-exon gene, and is predicted to replace an evolutionarily conserved glycine amino acid with aspartate at position 12 (p.Gly12Asp) in the encoded protein. The p.Gly12Asp variant has been demonstrated to confer oncogenic potential via inhibiting the GTPase activity that result in continuous GTP-bound, active state [PMID: 11323676, 27096871]. Although another variant at codon 12 (p.Gly12Ser) has been reported in the germline of individuals with RASopathy phenotypes [PMID: 17704260, 26242988], p.Gly12Asp variant has not been reported constitutionally. The p.Gly12Asp variant has recently been identified in CPAM sections of individuals at less than 35% variant allele fraction (VAF) while the nearby unaffected lung tissue sections were found to be not carrying the p.Gly12Asp variant [PMID: 35794233]. The c.35G>A variant has been found at 28% VAF (13/47 reads) in this fetal sample, which might reflect the tissue-limited mosaicism of respiratory tract cells present in the amniotic fluid. Based on available evidence this de novo mosaic c.35G>A p.Gly12Asp variant identified in KRAS is classified as Pathogenic." ], "review_description": "Pathogenic", "submitter_name": "New York Genome Center", "review_date": 20220719, "finding": [ { "symbols": { "hp": "HP:0010959" }, "normalized_phenotype": [ "Congenital Pulmonary Airway Malformation" ] }, { "symbols": { "hp": "HP:0000474" }, "normalized_phenotype": [ "Thickened Nuchal Skin Fold" ] }, { "symbols": { "hp": "HP:0001791" }, "normalized_phenotype": [ "Fetal Ascites" ] } ], "diseases": [ { "names": [ "Congenital Pulmonary Airway Malformations" ] } ], "method": "clinical testing", "date_updated": 20240519, "origin": "de novo", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005044128" } ], "submission_description": [], "review_date": 20220719, "diseases": [ { "names": [ "Congenital Pulmonary Airway Malformations" ] } ], "date_created": 20240519, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV004554600" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Capillary malformation-arteriovenous malformation 1", "submissions": [ { "submitter_date": 20210629, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School", "review_date": 20210501, "diseases": [ { "symbols": { "omim": "608354" } } ], "date_updated": 20220101, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001739511" } ], "submission_description": [], "review_date": 20210501, "diseases": [ { "symbols": { "orphanet": "137667", "omim": "608354", "medgen": "C4747394", "mondo": "MONDO:0020783" }, "names": [ "Capillary Malformation-Arteriovenous Malformation 1" ], "normalized_disease": [ "Capillary Malformation-Arteriovenous Malformation 1" ], "keyword": "RASA1-Related Disorders" } ], "date_created": 20220101, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV001799604" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Primary low grade serous adenocarcinoma of ovary", "submissions": [ { "submitter_date": 20191104, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "University Health Network, Princess Margaret Cancer Centre", "review_date": 20191104, "diseases": [ { "normalized_cancer": [ "Ovary/Fallopian Tube" ], "symbols": { "medgen": "C4302356" }, "names": [ "Primary Low Grade Serous Adenocarcinoma Ovary" ] } ], "method": "research", "date_updated": 20191129, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000999192" } ], "submission_description": [], "review_date": 20191104, "diseases": [ { "normalized_cancer": [ "Ovary/Fallopian Tube" ], "symbols": { "medgen": "C4302356" }, "names": [ "Primary Low Grade Serous Adenocarcinoma Ovary" ] } ], "date_created": 20191129, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000856666" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Carcinoma of pancreas", "submissions": [ { "submitter_date": 20190211, "submission_description": [ "Variant causes impairment of the intrinsic GTPase activity of KRAS and subsequent activation of downstream signaling pathways that drive cancer growth." ], "review_description": "Pathogenic", "submitter_name": "Laboratory for Clinical Genomics and Advanced Technology, Dartmouth-Hitchcock Medical Center", "review_date": 20190207, "finding": [ { "symbols": { "hp": "HP:0002894" }, "normalized_phenotype": [ "Neoplasm Of The Pancreas" ] } ], "diseases": [ { "symbols": { "omim": "260350" } } ], "method": "research", "date_updated": 20250803, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000882700" }, { "submitter_date": 20220309, "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20120610, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_disease": [ "Familial Pancreatic Carcinoma" ], "normalized_cancer": [ "Pancreas" ], "names": [ "Familial Pancreatic Carcinoma" ] } ], "method": "literature only", "date_updated": 20220312, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000033658" } ], "submission_description": [], "review_date": 20190207, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "pub_med": [ 17060676, 24493721, 25394175 ], "normalized_disease": [ "Exocrine Pancreatic Carcinoma", "Familial Pancreatic Carcinoma" ], "normalized_cancer": [ "Pancreas" ], "symbols": { "medgen": "C0235974", "orphanet": "1333", "mesh": "C562463", "mondo": "MONDO:0005192" }, "names": [ "Exocrine Pancreatic Carcinoma", "Pancreatic Acinar Carcinoma", "Exocrine Pancreatic Carcinoma", "Familial Pancreatic Carcinoma", "Familial Pancreatic Carcinoma", "Exocrine Pancreatic Carcinoma" ], "disease_mechanism": "loss of function" } ], "date_created": 20130404, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000013411" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Acute myeloid leukemia", "submissions": [ { "submitter_date": 20210421, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Hematopathology, The University of Texas M.D. Anderson Cancer Center", "review_date": 20180330, "diseases": [ { "normalized_disease": [ "Acute Myeloid Leukemia" ], "normalized_cancer": [ "Acute Myeloid Leukemia" ], "names": [ "Acute Myeloid Leukemia" ] } ], "method": "clinical testing", "date_updated": 20250413, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001571657" } ], "submission_description": [], "review_date": 20180330, "diseases": [ { "pub_med": [ 22138009, 23970018, 32171751 ], "normalized_disease": [ "Acute Myeloid Leukemia" ], "normalized_cancer": [ "Acute Myeloid Leukemia", "Acute non-lymphocytic leukemia", "Acute granulocytic leukemia", "Leukemia, acute myelogenous, somatic" ], "symbols": { "omim": "601626", "medgen": "C0023467", "orphanet": "519", "mesh": "D015470", "mondo": "MONDO:0018874", "human_phenotype_ontology": "HP:0006728" }, "names": [ "Acute Myeloid Leukemia", "Acute Myeloid Leukemia, Adult", "Aml Adult", "Acute Myeloid Leukemia", "Acute Myeloid Leukemia", "Acute Myeloid Leukemia", "Leukemia, Acute Myelogenous, Somatic" ], "disease_mechanism": "Constitutively activated FLT3" } ], "date_created": 20170308, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000433573" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Vascular Tumors Including Pyogenic Granuloma", "submissions": [ { "submitter_date": 20171127, "submission_description": [], "review_description": "Likely pathogenic", "submitter_name": "Yale Center for Mendelian Genomics, Yale University", "review_date": 20150219, "diseases": [ { "normalized_cancer": [ "Vascular Tumors Including Pyogenic Granuloma" ], "names": [ "Vascular Tumors Including Pyogenic Granuloma" ] } ], "method": "literature only", "date_updated": 20180714, "origin": "somatic", "clinical_significance": [ "Likely pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000784594" } ], "submission_description": [], "review_date": 20150219, "diseases": [ { "normalized_cancer": [ "Vascular Tumors Including Pyogenic Granuloma" ], "names": [ "Vascular Tumors Including Pyogenic Granuloma" ] } ], "date_created": 20180714, "clinical_significance": [ "Likely pathogenic" ], "review_description": "Likely pathogenic", "allele_id": 27621, "accession_id": "RCV000662266" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Ovarian neoplasm", "submissions": [ { "submitter_date": 20160426, "submission_description": [ "Somatic KRAS variants have been identified in up to 15% of cases of ovarian carcinoma, and Gly12Asp accounts for 40% of the identified KRAS variants (COSMIC 2010; Auner 2009)." ], "review_description": "Pathogenic", "submitter_name": "Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine", "review_date": 20140828, "diseases": [ { "symbols": { "omim": "167000" } } ], "method": "clinical testing", "date_updated": 20160529, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000198480" } ], "submission_description": [], "review_date": 20140828, "diseases": [ { "pub_med": [ 19042984, 22964825, 23188549, 33410258, 29450531 ], "normalized_disease": [ "Ovarian Neoplasm" ], "normalized_cancer": [ "Ovary/Fallopian Tube" ], "symbols": { "medgen": "C0919267", "mesh": "D010051", "mondo": "MONDO:0021068", "human_phenotype_ontology": "HP:0100615" }, "names": [ "Ovarian Neoplasm", "Ovarian Neoplasm", "Ovarian Neoplasm", "Ovarian Neoplasms" ] } ], "date_created": 20150130, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000150897" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Non-small cell lung carcinoma", "submissions": [ { "submitter_date": 20160426, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine", "review_date": 20140828, "diseases": [ { "symbols": { "medgen": "C0007131" } } ], "method": "clinical testing", "date_updated": 20160529, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000198479" }, { "submitter_name": "Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center", "submitter_date": 20190207, "submission_description": [], "review_description": "Pathogenic", "diseases": [ { "symbols": { "hp": "HP:0030358" } } ], "method": "research", "date_updated": 20250413, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000882686" } ], "submission_description": [], "review_date": 20140828, "diseases": [ { "pub_med": [ 24868098, 24673736, 24627688, 23667368, 30813707 ], "normalized_disease": [ "Non-Small Cell Lung Carcinoma" ], "normalized_cancer": [ "Non-Small Cell Lung Cancer" ], "symbols": { "medgen": "C0007131", "mesh": "D002289", "mondo": "MONDO:0005233", "human_phenotype_ontology": "HP:0030358" }, "names": [ "Non-Small Cell Lung Carcinoma", "Non-Small Cell Lung Carcinoma" ], "disease_mechanism": "Other" } ], "date_created": 20150130, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000150896" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Juvenile myelomonocytic leukemia", "submissions": [ { "submitter_date": 20160426, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine", "review_date": 20140828, "diseases": [ { "symbols": { "omim": "607785" } } ], "method": "clinical testing", "date_updated": 20160529, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000198478" }, { "submitter_date": 20220309, "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20120610, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_disease": [ "Juvenile Myelomonocytic Leukemia" ], "normalized_cancer": [ "Juvenile Myelomonocytic Leukemia" ], "names": [ "Juvenile Myelomonocytic Leukemia" ] } ], "method": "literature only", "date_updated": 20220312, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000191996" } ], "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_date": 20140828, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "pub_med": [ 24493721 ], "normalized_cancer": [ "Juvenile Myelomonocytic Leukemia" ], "symbols": { "orphanet": "86834", "omim": "607785", "medgen": "C0349639", "mondo": "MONDO:0011908", "human_phenotype_ontology": "HP:0012209" }, "names": [ "Juvenile Myelomonocytic Leukemia", "Juvenile Myelomonocytic Leukemia" ], "normalized_disease": [ "Juvenile Myelomonocytic Leukemia" ], "keyword": "Hereditary cancer syndrome" } ], "date_created": 20141122, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000144969" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Nevus sebaceous", "submissions": [ { "submitter_date": 20171101, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Yale Center for Mendelian Genomics, Yale University", "review_date": 20121025, "diseases": [ { "names": [ "Nevus Sebaceous" ] } ], "method": "literature only", "date_updated": 20151011, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000611562" }, { "submitter_date": 20220309, "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20120610, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_cancer": [ "NEVUS SEBACEOUS, SOMATIC" ], "names": [ "Nevus Sebaceous, Somatic" ] } ], "method": "literature only", "date_updated": 20220312, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000051860" } ], "submission_description": [], "review_date": 20121025, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_cancer": [ "NEVUS SEBACEOUS, SOMATIC" ], "symbols": { "medgen": "C3854181", "human_phenotype_ontology": "HP:0010815" }, "names": [ "Nevus Sebaceous", "Nevus Sebaceous, Somatic" ] } ], "date_created": 20130404, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000029214" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Epidermal nevus", "submissions": [ { "submitter_date": 20220309, "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20120610, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_disease": [ "Nevus, Epidermal" ], "normalized_cancer": [ "EPIDERMAL NEVUS, SOMATIC" ], "names": [ "Nevus, Epidermal" ] } ], "method": "literature only", "date_updated": 20220312, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000044088" } ], "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_date": 20120610, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_cancer": [ "Nevus, epidermal, somatic" ], "symbols": { "orphanet": "79414", "omim": "162900", "medgen": "C0334082", "mondo": "MONDO:0008093", "human_phenotype_ontology": "HP:0010816" }, "names": [ "Nevus, Epidermal", "Nevus, Epidermal", "Nevus, Epidermal" ], "normalized_disease": [ "Nevus, Epidermal" ], "keyword": "Hereditary cancer syndrome" } ], "date_created": 20130404, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV000022799" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Gastric cancer", "submissions": [ { "submitter_date": 20220309, "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20120610, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_disease": [ "Gastric Cancer" ], "normalized_cancer": [ "Esophagus/Stomach" ], "names": [ "Gastric Cancer" ] } ], "method": "literature only", "date_updated": 20220312, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000033659" } ], "submission_description": [ "Pancreatic Carcinoma, Somatic", "Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.", "Gastric Cancer, Somatic", "Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.", "Epidermal Nevus, Somatic", "Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.", "Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.", "Nevus Sebaceous, Somatic", "Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).", "Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic", "The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.", "Juvenile Myelomonocytic Leukemia, Somatic", "In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.", "RAS-associated Autoimmune Leukoproliferative Disorder, Somatic", "In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene." ], "review_date": 20120610, "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "diseases": [ { "normalized_disease": [ "Gastric Cancer" ], "normalized_cancer": [ "Esophagus/Stomach", "Malignant Tumor" ], "symbols": { "omim": "613659", "medgen": "C0024623", "mesh": "D013274", "mondo": "MONDO:0001056", "human_phenotype_ontology": "HP:0012126" }, "names": [ "Gastric Cancer", "Gastric Cancer", "Gastric Cancer" ] } ], "date_created": 20230107, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 27621, "accession_id": "RCV002508117" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND multiple conditions", "submissions": [ { "submitter_name": "Martignetti Lab, Icahn School of Medicine at Mount Sinai", "submitter_date": 20230913, "submission_description": [], "review_description": "association", "finding": [ { "names": [ "Atypical Endometrial Hyperplasia" ] } ], "diseases": [ { "symbols": { "mondo": "MONDO:0006096" } }, { "symbols": { "mondo": "MONDO:0006193" } } ], "method": "research", "date_updated": 20250413, "origin": "somatic", "clinical_significance": [ "association" ], "review_status": "no assertion criteria provided", "accession_id": "SCV004035006" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Endometrial Hyperplasia without Atypia" ], "symbols": { "medgen": "C1516855", "mondo": "MONDO:0006193" }, "names": [ "Endometrial Hyperplasia without Atypia" ] }, { "normalized_disease": [ "Atypical Endometrial Hyperplasia" ], "symbols": { "medgen": "C0349579", "mondo": "MONDO:0006096" }, "names": [ "Atypical Endometrial Hyperplasia" ] } ], "date_created": 20230916, "clinical_significance": [ "association" ], "review_description": "association", "allele_id": 27621, "accession_id": "RCV003327361" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Neoplasm", "submissions": [ { "submitter_date": 20250304, "submission_description": [], "submitter_name": "Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital", "review_date": 20250304, "diseases": [ { "symbols": { "medgen": "C0027651" } } ], "method": "clinical testing", "date_updated": 20250311, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV005094257" } ], "submission_description": [], "diseases": [ { "pub_med": [ 22918138, 23619274, 34131312 ], "normalized_cancer": [ "Neoplasm", "Neoplasms", "Neoplasm (disease)", "tumor" ], "symbols": { "medgen": "C0027651", "mesh": "D009369", "mondo": "MONDO:0005070", "human_phenotype_ontology": "HP:0006741" }, "names": [ "Neoplasm", "Neoplasms", "Neoplasm", "Neoplasm" ], "normalized_disease": [ "Neoplasm" ], "keyword": "neoplasm" } ], "date_created": 20240811, "clinical_significance": [], "allele_id": 27621, "accession_id": "RCV004668724" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Encephalocraniocutaneous lipomatosis", "submissions": [ { "submitter_name": "GeneReviews", "submitter_date": 20220225, "submission_description": [], "review_description": "not provided", "diseases": [ { "symbols": { "medgen": "C0406612" } } ], "method": "literature only", "date_updated": 20221001, "origin": "somatic", "clinical_significance": [ "not provided" ], "review_status": "no classification provided", "accession_id": "SCV002099547" } ], "submission_description": [], "diseases": [ { "symbols": { "orphanet": "2396", "omim": "613001", "medgen": "C0406612", "mondo": "MONDO:0013074" }, "names": [ "Encephalocraniocutaneous Lipomatosis" ], "normalized_disease": [ "Encephalocraniocutaneous Lipomatosis" ], "keyword": "Neoplasm" } ], "date_created": 20220303, "clinical_significance": [ "not provided" ], "review_description": "not provided", "allele_id": 27621, "accession_id": "RCV001839445" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Colorectal cancer", "submissions": [ { "submitter_date": 20250509, "submission_description": [ "Missense, Gain-of-function" ], "submitter_name": "Department of Clinical Biochemistry, Naestved Hospital", "review_date": 20241010, "diseases": [ { "symbols": { "mondo": "MONDO:0005575" } } ], "method": "research", "date_updated": 20251115, "origin": "somatic", "clinical_significance": [], "review_status": "no assertion criteria provided", "accession_id": "SCV006076878" } ], "submission_description": [], "diseases": [ { "pub_med": [ 26389505, 26389258, 34043773 ], "normalized_disease": [ "Colorectal Cancer" ], "normalized_cancer": [ "Colorectal cancer", "Colorectal cancer, somatic", "Malignant Colorectal Neoplasm" ], "symbols": { "omim": "114500", "medgen": "C0346629", "mondo": "MONDO:0005575" }, "names": [ "Colorectal Cancer", "Colorectal Cancer", "Colorectal Cancer" ] } ], "date_created": 20251115, "clinical_significance": [], "allele_id": 27621, "accession_id": "RCV006250158" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Precursor B-cell acute lymphoblastic leukemia", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in precursor B-cell acute lymphoblastic leukemia, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 26037647, 20570890). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 32154130, 25961940, 25917266, 27872090)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20231012, "diseases": [ { "symbols": { "mondo": "MONDO:0020511" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105406" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Precursor B-Cell Acute Lymphoblastic Leukemia" ], "normalized_cancer": [ "B-Lymphoblastic Leukemia/Lymphoma" ], "symbols": { "medgen": "C0349636", "mondo": "MONDO:0020511", "human_phenotype_ontology": "HP:0004812" }, "names": [ "Precursor B-Cell Acute Lymphoblastic Leukemia", "Pre-B-Cell Acute Lymphoblastic Leukemia", "B Acute Lymphoblastic Leukemia" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 27621, "accession_id": "RCV006253518" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Papillary thyroid carcinoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in thyroid gland papillary carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 20570890, 26037647). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 25417114, 20824721, 20526288, 22150560, 23625203, 27494611, 32495721, 31540418)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20241224, "diseases": [ { "symbols": { "mondo": "MONDO:0005075" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105422" } ], "submission_description": [], "diseases": [ { "pub_med": [ 26389271, 26389258 ], "normalized_disease": [ "Thyroid Gland Papillary Carcinoma" ], "normalized_cancer": [ "Papillary Thyroid Cancer" ], "symbols": { "medgen": "C0238463", "orphanet": "146", "mesh": "D000077273", "mondo": "MONDO:0005075", "human_phenotype_ontology": "HP:0002895" }, "names": [ "Thyroid Gland Papillary Carcinoma", "Nonmedullary Thyroid Carcinoma, Papillary", "Thyroid Carcinoma, Papillary, Somatic", "Thyroid Gland Papillary Carcinoma" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 27621, "accession_id": "RCV006253519" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Alveolar rhabdomyosarcoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in alveolar rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 20570890, 26037647). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 24436047, 34166060, 26138366, 24332040)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20240709, "diseases": [ { "symbols": { "mondo": "MONDO:0009994" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105413" } ], "submission_description": [], "diseases": [ { "pub_med": [ 21829230 ], "normalized_disease": [ "Alveolar Rhabdomyosarcoma" ], "normalized_cancer": [ "Alveolar Rhabdomyosarcoma" ], "symbols": { "orphanet": "780", "omim": "268220", "medgen": "C0206655", "mondo": "MONDO:0009994", "human_phenotype_ontology": "HP:0006779" }, "names": [ "Alveolar Rhabdomyosarcoma", "Alveolar Rhabdomyosarcoma", "Alveolar Rhabdomyosarcoma" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 27621, "accession_id": "RCV006253520" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Glioma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in glioma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 20570890, 26037647). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 32289278, 23817572, 29880043, 28912153, 37524847, 30710203)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20250324, "diseases": [ { "symbols": { "mondo": "MONDO:0021042" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105432" } ], "submission_description": [], "diseases": [ { "pub_med": [ 22138009 ], "normalized_disease": [ "Glioma" ], "normalized_cancer": [ "Glioma" ], "symbols": { "medgen": "C0017638", "mesh": "D005910", "mondo": "MONDO:0021042", "human_phenotype_ontology": "HP:0009733" }, "names": [ "Glioma" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 27621, "accession_id": "RCV006253521" }, { "variation_id": 12582, "variant_id": 10190120253982840004, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Embryonal rhabdomyosarcoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 20570890, 26037647, 15093544). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24436047, 34166060, 25768946, 19681119, 24332040, 26138366)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20250408, "diseases": [ { "symbols": { "mondo": "MONDO:0009993" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single 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"disease_alt_symbol": null, "evidences": null }, { "disease": "Adenomas and Adenocarcinomas", "disease_description": "From tissue: Middle lobe, lung", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Adenomas and Adenocarcinomas", "disease_description": "From tissue: Overlapping lesion of lung", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Adenomas and Adenocarcinomas", "disease_description": "From tissue: Prostate gland", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Adenomas and Adenocarcinomas", "disease_description": "From tissue: Rectosigmoid junction", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Adenomas and Adenocarcinomas", "disease_description": "From tissue: Splenic flexure of colon", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Atypical endometrial hyperplasia", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Autoimmune lymphoproliferative syndrome type 4", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Capillary malformation-arteriovenous malformation 1 ", "disease_description": "Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is characterized by the presence of multiple small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 21348050 ], "cosmic_study": null } }, { "disease": "Carcinoma of pancreas", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Cardiofaciocutaneous syndrome 2 ", "disease_description": "Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis).", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 20301365 ], "cosmic_study": null } }, { "disease": "Cerebral arteriovenous malformation ", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Colorectal Cancer", "disease_description": "While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. 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Tail of pancreas", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Ductal and Lobular Neoplasms", "disease_description": "From tissue: Pancreas, NOS;Pancreas, NOS", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Ductal and Lobular Neoplasms", "disease_description": "From tissue: Pancreas, NOS", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Ductal and Lobular Neoplasms", "disease_description": "From tissue: Head of pancreas", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Ductal and Lobular Neoplasms", "disease_description": "From tissue: Body of pancreas", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Ductal and Lobular Neoplasms", "disease_description": "From tissue: Breast, NOS", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Encephalocraniocutaneous lipomatosis ", "disease_description": "Encephalocraniocutaneous lipomatosis (ECCL) comprises a spectrum of predominantly congenital anomalies.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 35099867 ], "cosmic_study": null } }, { "disease": "Endometrial hyperplasia without atypia", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Epidermal nevus", "disease_description": "PIK3CA-related overgrowth spectrum (PROS) encompasses a range of clinical findings in which the core features are congenital or early-childhood onset of segmental/focal overgrowth with or without cellular dysplasia.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 23946963 ], "cosmic_study": null } }, { "disease": "Familial cancer of breast", "disease_description": "BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (including fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Familial pancreatic carcinoma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Gastric cancer", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Gastric cancer ", "disease_description": "A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 3034404, 7773929, 14534542 ], "cosmic_study": null } }, { "disease": "Gliomas", "disease_description": "From tissue: Brain, NOS", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Juvenile myelomonocytic leukemia ", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "KRAS-related overgrowth", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Leukemia, juvenile myelomonocytic ", "disease_description": "An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 17332249 ], "cosmic_study": null } }, { "disease": "Linear nevus sebaceous syndrome", "disease_description": "Schimmelpenning-Feuerstein-Mims syndrome, also known as linear sebaceous nevus syndrome, is characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects (summary by Happle, 1991 and Ernst et al.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Lung cancer", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Lymphoid Leukemias", "disease_description": "From tissue: Bone marrow", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Lymphoid Leukemias", "disease_description": "From tissue: Blood", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Malignant tumor of urinary bladder", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Myeloid Leukemias", "disease_description": "From tissue: Bone marrow", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Neoplasm", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 22918138, 23619274 ], "cosmic_study": null } }, { "disease": "Neoplasms, NOS", "disease_description": "From tissue: Breast, NOS;Pancreas, NOS", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Nevi and Melanomas", "disease_description": "From tissue: Skin, NOS", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Non-small cell lung carcinoma ", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 24673736, 24868098 ], "cosmic_study": null } }, { "disease": "Noonan syndrome 3 ", "disease_description": "Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 20301303 ], "cosmic_study": null } }, { "disease": "Ovarian neoplasm", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Plasma Cell Tumors", "disease_description": "From tissue: Bone marrow", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Primary low grade serous adenocarcinoma of ovary", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "RASopathy", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Schimmelpenning-Feuerstein-Mims syndrome ", "disease_description": "A disease characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects. Many oral manifestations have been reported, not only including hypoplastic and malformed teeth, and mucosal papillomatosis, but also ankyloglossia, hemihyperplastic tongue, intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts, follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi follow the lines of Blaschko and these can continue as linear intraoral lesions, as in mucosal papillomatosis.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 30891959 ], "cosmic_study": null } }, { "disease": "Squamous Cell Neoplasms", "disease_description": "From tissue: Cervix uteri", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Thymic Epithelial Neoplasms", "disease_description": "From tissue: Thymus", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Toriello-Lacassie-Droste syndrome", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Transitional Cell Papillomas and Carcinomas", "disease_description": "From tissue: Bladder, NOS", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Transitional Cell Papillomas and Carcinomas", "disease_description": "From tissue: Lateral wall of bladder", "disease_symbol": null, "disease_alt_symbol": null, "evidences": null }, { "disease": "Vascular Tumors Including Pyogenic Granuloma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} } ], "siftscore": null, "siftprediction": null, "polyphenscore": null, "polyphenprediction": null, "evidences": { "pub_med_references": [ 7773929, 8439212, 16533793, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711, 29298116, 30891959, 34820593 ], "cosmic_study": [] }, "xrefs": { "cosmicmutationid": [ "COSV55497369", "COSV55865099" ], "clinvaraccession": [] }, "variant_type": "Disease", "disease": "Acute Lymphoblastic Leukemia", "disease_symbol": null, "disease_alt_symbol": null, "bed_comments": null, "pub_med_references": [ 7773929, 8439212, 16533793, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711, 29298116, 30891959, 34820593 ] } ] } ], "wustl_civic": [ { "version": "07-Oct-2025", "items": [ { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": null, "drugs": [ "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/91", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "In a patient with V600E-positive NSCLC, KRAS G12D seemed to confer resistance to dabrafenib.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-11-24 19:49:00 UTC", "nct_ids": null, "normalized_drug": [ "Dabrafenib" ], "phenotypes": null, "pub_med_references": [ 23524406 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": "CA122538", "variant_groups": [ { "group": "EGFR TKI Resistance", "group_details": { "description": "EGFR pathway activation is a nearly ubiquitous hallmark of cancer. Many tyrosine kinase inhibitors have been developed to target EGFR pathway activity. One such inhibitor, erlotinib, has demonstrated efficacy in an EGFR over-active setting. However, the T790M missense mutation has shown to confer resistance to this inhibitor in cell lines and case studies.", "variant_group_civic_url": "https://civicdb.org/links/variant_groups/12" } } ], "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Positive", "disease": "Lung Cancer", "doid": "1324", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/228", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "KRAS G12D mutation occurs in never smokers significantly more often than in smokers.", "evidence_status": "accepted", "evidence_type": "Diagnostic", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 23014527 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": null, "drugs": [ "Selumetinib", "Dactolisib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/305", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "The use of NVP-BEZ235 in conjunction with ARRY-142886, but not as monotherapy, in a lung cancer model with KRAS G12D mutation led to marked tumor regression.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Dactolisib", "Selumetinib" ], "phenotypes": null, "pub_med_references": [ 19029981 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Pancreatic Carcinoma", "doid": "4905", "drug_interaction_type": null, "drugs": [ "Akt Inhibitor MK2206" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/937", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "Among 33 patients treated with pan-AKT inhibitor MK-2206 in this phase 1 study, one patient with pancreatic adenocarcinoma and PTEN loss and a KRAS G12D mutation experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Akt Inhibitor Mk2206" ], "phenotypes": null, "pub_med_references": [ 22025163 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Better Outcome", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1215", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In 119 metastatic colorectal cancer patients treated with cetuximab-based first-line chemotherapy, KRAS G12D mutations (N=44) were associated with longer overall patient survival when compared to other KRAS G12 mutations (23.3 vs 14-18 months; G12V, A, C, S, R).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 22948721 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Pancreatic Cancer", "doid": "1793", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1300", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In 219 patients with metastatic pancreatic ductal adenocarcinoma, a multivariate analysis identified KRAS G12D mutations as an independent predictor of poorer prognosis both in patients that have received chemotherapy (N=49/162), and the entire series (N=73/219). HR of 1.84 (P=0.02) and 1.44 (P=0.01), respectively.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 27010960 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Malignant Exocrine Pancreas Neoplasm", "doid": "1795", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1311", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In 171 patients with tumors of the exocrine pancreas, a KRAS G12D mutation (N=60) was associated with shorter overall survival than being wild-type for KRAS (N=21; Hazard Ratio: 95% CI between 1.14 and 2.67). Additionally, KRAS mutations combined with CDKN2A alterations (N=26) showed an even worse OS than those wild-type for both (N=17; HR: 95%CI 1.33-7.10).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 23565280 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Hairy Cell Leukemia", "doid": "285", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1580", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "One patient enrolled in a clinical study to evaluate vemurafenib treatment of BRAF V600E mutant hairy-cell leukemia developed resistance to vemurafenib retreatment. 300-gene targeted sequencing of the patient’s genome revealed activating subclonal KRAS mutations (KRAS G12D, 15.2% allele frequency; KRAS K117N, 1.2%), as well as a RUNX1 A55E mutation (5.9%) that had not been seen prior to vemurafenib treatment or at remission. BRAF V600E allele frequency was detectable (2.4%) at the time of remission but dramatically increased at relapse (64.9%).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": [ "NCT01711632" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 26352686 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Pancreatic Ductal Carcinoma", "doid": "3587", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1732", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Exon-2 KRAS mutation status was analyzed in 219 patients with pancreatic ductal carcinoma, excluding those who had previously undergone chemotherapy, first-line pancreatic resection, or neoadjuvant treatment with chemotherapy or radiotherapy. 72 patients had wild-type KRAS, 147 had a codon-12 KRAS mutation (G12D, G12V, or G12R) and 73 had a G12D KRAS mutation, specifically. There was no significant difference in overall survival between wild-type patients and patients with any type of exon-12 mutation. However, patients with the G12D mutation exhibited significantly lower overall survival compared to wild-type patients in univariate and multivariate analyses. This difference in overall survival between wild-type and G12D patients persisted in the subset of patients who underwent chemotherapy at any point after enrollment.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 27010960 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Therapeutic Tumor Infiltrating Lymphocytes" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1898", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "A patient with metastatic colorectal cancer was enrolled in a phase 2 clinical trial (NCT01174121). 24 cultures of tumor-infiltrating lymphocytes were expanded from 3 lung metastasis resections. After cultures were tested for reactivity, the patient was infused with 1.48 x 10^11 tumor-infiltrating lymphocytes (75% CD8+ T cells) that were specifically reactive to KRAS G12D. All 7 metastatic lung lesions regressed 40 days after therapy, and the patient had a 9-month partial response.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 27959684 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Panitumumab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2193", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "One patient participating in a large retrospective study of EGFR monoclonal antibodies in metastatic, treatment refractory colorectal cancer had a tumor which harbored KRAS G12D, was wildtype for NRAS, BRAF and PIK3CA, and had individual response data. This patient was was a 55 year old female treated with panitumumab monotherapy as 3rd line therapy who experienced progressive disease (PFS: 8 weeks; OS: 9 weeks).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Panitumumab" ], "phenotypes": null, "pub_med_references": [ 20619739 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Cetuximab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2207", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "This was a retrospective study of 691 cetuximab treated patients with metastatic colorectal cancer. Of those, 76 patients harbored KRAS G12D, were BRAF, NRAS and PIK3CA wt, and had individual response data. Five patients had partial response, 34 had stable disease, and 37 progressed. Treatments included cetuximab + irinotecan (n=61), cetuximab + FOLFIRI (n=6), cetuximab monotherapy (n=5), cetuximab + oxaliplatin + 5FU (n=2), cetuximab + 5FU (n=1), cetuximab + oxaliplatin + bevacizumab (n=1). Median PFS was 12 weeks (3-169 weeks), median OS was 31 weeks (6-232 weeks), and median number of previous chemotherapy lines was 2 (0-5). Median age was 62 years old (32-86), and there were 43 males and 33 females. Using these data and data from the larger cohort, authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Cetuximab" ], "phenotypes": null, "pub_med_references": [ 20619739 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Selumetinib", "Dactolisib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2218", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring KRAS, NRAS, BRAF or PIK3CA mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors studied had KRAS mutations with 9 G12D (2 with PIK3CA H1047R) and 13 other G12 mutations.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Dactolisib", "Selumetinib" ], "phenotypes": null, "pub_med_references": [ 22392911 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Panitumumab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2236", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": [ "NCT00113763", "NCT00113776" ], "normalized_drug": [ "Panitumumab" ], "phenotypes": null, "pub_med_references": [ 18316791 ], "rating": null, "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Lung Cancer", "doid": "1324", "drug_interaction_type": null, "drugs": [ "Gefitinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2240", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Gefitinib" ], "phenotypes": null, "pub_med_references": [ 17409929 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Multiple Myeloma", "doid": "9538", "drug_interaction_type": null, "drugs": [ "Melphalan" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2250", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Melphalan" ], "phenotypes": null, "pub_med_references": [ 11050000 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Multiple Myeloma", "doid": "9538", "drug_interaction_type": null, "drugs": [ "Melphalan" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2251", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Melphalan" ], "phenotypes": null, "pub_med_references": [ 12483530 ], "rating": null, "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Multiple Myeloma", "doid": "9538", "drug_interaction_type": null, "drugs": [ "Melphalan" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2252", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Melphalan" ], "phenotypes": null, "pub_med_references": [ 16497971 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Regorafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3946", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12D mutation demonstrated resistance to regorafenib treatment (IC50: 195.01nM vs. 114.28 nM P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G12D was more resistant to regorafenib than KRAS wt, and intermediately resistant compared to other common KRAS G12/G13 mutations.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Regorafenib" ], "phenotypes": null, "pub_med_references": [ 26161928 ], "rating": "1", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3957", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In vitro studies of M229 (a human melanoma cell line) endogenously expressing wildtype KRAS and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express KRAS4a G12D or KRAS4b G12D were more resistant to vemurafenib (a BRAF inhibitor) than cells transduced with empty vectors (90% vs 10% survival).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 24265155 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Ovarian Cancer", "doid": "2394", "drug_interaction_type": null, "drugs": [ "Cetuximab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3958", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In an in vitro study, a MCAS cell line expressing KRAS G12D mutation was associated with reduced sensitivity to cetuximab treatment as compared to RMUG-L and OMC-1 cells expressing wild-type KRAS. Resistance was determined by assessing cell growth. Further, in an in vivo experiment, KRAS G12D expressing MCAS xenografts in nude mice had reduced response to cetuximab, as compared to KRAS wild-type expressing RMUG-L xenografts. Resistance was determined by assessing tumor growth.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Cetuximab" ], "phenotypes": null, "pub_med_references": [ 22246397 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Panitumumab", "Cetuximab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/6316", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS, PIK3CA, and PTEN were tested for mutation; KRAS G12D was the only variant noted in the primary tumor of two patients who experienced stable disease following treatment (Patients 22 and 36; colon and rectum tumors; Supplemental Table 1). In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "KRAS", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:27 UTC", "nct_ids": null, "normalized_drug": [ "Cetuximab, Panitumumab" ], "phenotypes": null, "pub_med_references": [ 19223544 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "G12D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/79", "molecular_profiles": null } ] } ], "nih_gdc": [ { "version": "07-Jun-2025", "sex": [ { "key": "Male", "value": 101 }, { "key": "Female", "value": 97 } ], "age_freq": [ { "key": "60-70", "value": 62 }, { "key": "70-80", "value": 58 }, { "key": "50-60", "value": 37 }, { "key": "80-90", "value": 20 }, { "key": "40-50", "value": 17 }, { "key": "30-40", "value": 2 }, { "key": "90-100", "value": 2 } ], "os_status": [ { "key": "Living", "value": 148 }, { "key": "Deceased", "value": 50 } ], "race": [ { "key": "White", "value": 132 }, { "key": "Black Or African American", "value": 23 }, { "key": "Asian", "value": 11 }, { "key": "Native Hawaiian Or Other Pacific Islander", "value": 1 } ], "tumor_status": [ { "key": "Disease Free", "value": 96 }, { "key": "Recurred", "value": 70 } ], "tumor_tissue_site": null, "path_t_stage": [ { "key": "T3", "value": 91 }, { "key": "T2", "value": 21 }, { "key": "T4", "value": 11 }, { "key": "T1", "value": 7 }, { "key": "T4A", "value": 6 }, { "key": "T4B", "value": 5 }, { "key": "T1B", "value": 4 }, { "key": "T1A", "value": 3 }, { "key": "T2A", "value": 3 }, { "key": "T3B", "value": 3 }, { "key": "T1B1", "value": 2 }, { "key": "T2B", "value": 2 }, { "key": "T1C", "value": 1 }, { "key": "T2A2", "value": 1 }, { "key": "T3A", "value": 1 } ], "path_n_stage": [ { "key": "N0", "value": 73 }, { "key": "N1", "value": 54 }, { "key": "N2", "value": 14 }, { "key": "N1B", "value": 7 }, { "key": "Nx", "value": 5 }, { "key": "N2B", "value": 3 }, { "key": "N1A", "value": 2 }, { "key": "N1C", "value": 1 } ], "path_m_stage": [ { "key": "M0", "value": 91 }, { "key": "Mx", "value": 50 }, { "key": "M1", "value": 11 }, { "key": "M1A", "value": 3 }, { "key": "M1B", "value": 1 } ], "clin_t_stage": [ { "key": "T2", "value": 2 }, { "key": "T1", "value": 1 }, { "key": "T1A", "value": 1 }, { "key": "T3A", "value": 1 } ], "clin_n_stage": [ { "key": "N0", "value": 1 }, { "key": "Nx", "value": 1 } ], "clin_m_stage": [ { "key": "M0", "value": 3 } ], "ajcc_pathologic_tumor_stage": [ { "key": "Stage Iib", "value": 38 }, { "key": "Stage Iia", "value": 23 }, { "key": "Stage Iv", "value": 15 }, { "key": "Stage I", "value": 14 }, { "key": "Stage Ii", "value": 14 }, { "key": "Stage Iiib", "value": 10 }, { "key": "Stage Ib", "value": 9 }, { "key": "Stage Iii", "value": 7 }, { "key": "Stage Ia", "value": 6 }, { "key": "Stage Iiia", "value": 6 }, { "key": "Stage Iiic", "value": 6 }, { "key": "Stage Iva", "value": 4 }, { "key": "Stage Ivb", "value": 1 } ], "total_samples": 198, "study_name": null, "prior_dx": [ { "key": "No", "value": 175 }, { "key": "Yes", "value": 14 }, { "key": "Yes, History Of Prior Malignancy", "value": 6 }, { "key": "Yes, History Of Synchronous/Bilateral Malignancy", "value": 1 } ], "drug": null, "measure_of_response": [ { "key": "Clinical Progressive Disease", "value": 33 }, { "key": "Complete Response", "value": 29 }, { "key": "Stable Disease", "value": 6 }, { "key": "Partial Response", "value": 3 } ], "therapy_type": [ { "key": "Chemotherapy", "value": 146 }, { "key": "Other, Specify In Notes", "value": 11 }, { "key": "Ancillary", "value": 6 }, { "key": "Targeted Molecular Therapy", "value": 6 }, { "key": "Hormone Therapy", "value": 3 } ], "route_of_administration": [ { "key": "Iv", "value": 59 }, { "key": "Po", "value": 7 }, { "key": "Ih", "value": 1 }, { "key": "Im", "value": 1 }, { "key": "Sc", "value": 1 } ], "therapy_ongoing": [ { "key": "NO", "value": 156 }, { "key": "YES", "value": 15 } ], "clinical_significance": [ { "key": "Likely Pathogenic", "value": 198 }, { "key": "Pathogenic", "value": 198 } ], "pub_med_references": [ 2278970, 3122217, 7773929, 8439212, 12460918, 15696205, 15842656, 16361624, 16434492, 16618717, 17332249, 17384584, 17704260, 17910045, 18316791, 18794081, 19018267, 19029981, 19047918, 19075190, 19114683, 19255327, 19358724, 19679400, 19773371, 19794967, 19881948, 20609353, 20805368, 20921462, 20921465, 20949522, 21079152, 21169357, 21228335, 21398618, 21975775, 22025163, 22235099, 22282465, 22407852, 22499344, 22683711, 22897852, 23014527, 23182985, 23406027, 25044103, 25157968, 26372703, 27872090, 29298116, 29525983, 29721857, 30463544, 31949278 ], "oncotree_code": [ { "key": "PANCREAS", "value": 45 }, { "key": "COAD", "value": 44 }, { "key": "BOWEL", "value": 11 }, { "key": "LAIS", "value": 10 }, { "key": "STOMACH", "value": 9 }, { "key": "READ", "value": 8 }, { "key": "LUNG", "value": 8 }, { "key": "BLADDER", "value": 6 }, { "key": "KIDNEY", "value": 3 }, { "key": "STAD", "value": 3 }, { "key": "CERVIX", "value": 3 }, { "key": "HCC", "value": 2 }, { "key": "GBM", "value": 2 }, { "key": "UCS", "value": 2 }, { "key": "HEAD_NECK", "value": 1 }, { "key": "PROSTATE", "value": 1 }, { "key": "DSTAD", "value": 1 }, { "key": "CESC", "value": 1 }, { "key": "THYM", "value": 1 } ], "cancer_name": [ { "key": "Colon Adenocarcinoma", "value": 44 }, { "key": "Pancreas-Adenocarcinoma Ductal Type", "value": 43 }, { "key": "Endometrioid endometrial adenocarcinoma", "value": 32 }, { "key": "Lung Adenocarcinoma- Not Otherwise Specified (NOS)", "value": 10 }, { "key": "Colon Mucinous Adenocarcinoma", "value": 9 }, { "key": "Rectal Adenocarcinoma", 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29298116 ], "pub_med_references": [ 16533793, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711, 29298116, 30891959, 34820593 ], "disease_name": [ "Acute Lymphoblastic Leukemia", "Acute Lymphoblastic Leukemia", "Acute myeloid leukemia", "Adenomas and Adenocarcinomas", "Adenomas and Adenocarcinomas" ], "annotation_id": "VAR_016026" } ] } } ] } ], "alpha_missense": [ { "version": "03-Jul-2024", "main_data": "Likely Pathogenic", "alpha_missense_score": 0.9983977782525102 } ], "acmg_annotation": { "version_name": "13.14.0", "gene_symbol": "KRAS", "transcript": "NM_004985.5", "transcript_reason": "MANE select", "coding_impact": "missense", "blosum_score": -4, "verdict": { "ACMG_rules": { "benign_score": 0, "benign_subscore": "Uncertain Significance", "clinical_score": 5.265, "pathogenic_score": 15, "pathogenic_subscore": "Pathogenic", "total_score": 15, "verdict": "Pathogenic" }, "classifications": [ "PS3_Very Strong", "PM1", "PM5", "PP5_Moderate", "PM2_Supporting" ] }, "classifications": [ { "name": "PS3", "met_criteria": true, "user_explain": [ "Combined evidence strength is Very Strong (score = 9). .", "Very Strong: ClinVar classifies this variant as Pathogenic, 2 stars (reviewed Dec '25, 47 submissions of which 4 are from high confidence submitters), backed by functional studies (requires user validation) mentioned in 2 articles (%%PUBMED:29298116%% and %%PUBMED:21079152%%), and also citing 10 articles (%%PUBMED:35794233%%, %%PUBMED:34114335%%, %%PUBMED:31891627%%, %%PUBMED:31836588%%, %%PUBMED:30936194%%, and 5 more).", "Supporting: UniProt Variants classifies this variant as Pathogenic, backed by functional studies (requires user validation) mentioned in 2 articles (%%PUBMED:29298116%% and %%PUBMED:21079152%%), and also citing 9 articles (%%PUBMED:34820593%%, %%PUBMED:30891959%%, %%PUBMED:22683711%%, %%PUBMED:22499344%%, %%PUBMED:20949522%%, and 4 more), associated with Acute Lymphoblastic Leukemia." ], "strength": "Very Strong" }, { "name": "PM1", "met_criteria": true, "user_explain": [ "Hot-spot of length 17 amino-acids has 53 missense/in-frame variants (30 pathogenic variants, 23 uncertain variants, and no benign), which qualifies as strong pathogenic.", "UniProt protein RASK_HUMAN binding site 'Other binding site_10-18' has 37 missense/in-frame variants (24 pathogenic variants, 13 uncertain variants, and no benign), which qualifies as moderate pathogenic.", "Limiting strength to Moderate due to co-occurrence with other predictive evidence." ] }, { "name": "PM5", "met_criteria": true, "user_explain": [ "Alternative variant ##chr12:25398285 C⇒T## (Gly12Ser) is classified Pathogenic, 2 stars, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr12:25398285 C⇒G## (Gly12Arg) is classified Pathogenic, 2 stars, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr12:25398285 C⇒A## (Gly12Cys) is classified Likely Pathogenic, 1 star, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr12:25398284 C⇒G## (Gly12Ala) is classified Pathogenic, 2 stars, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr12:25398284 C⇒A## (Gly12Val) is classified Pathogenic, 2 stars, by ClinVar (confirmed using the germline classifier).", "5 pathogenic alternative variants identified.", "Limiting strength to Moderate due to co-occurrence with other predictive evidence." ] }, { "name": "PP5", "met_criteria": true, "user_explain": [ "Moderate: the VarSome community has classified this variant as Pathogenic, citing 17 articles (%%PUBMED:35075146%%, %%PUBMED:33917572%%, %%PUBMED:33538228%%, %%PUBMED:32810914%%, %%PUBMED:31409810%%, and 12 more)." ], "strength": "Moderate" }, { "name": "PM2", "met_criteria": true, "user_explain": [ "Variant not found in gnomAD genomes, good gnomAD genomes coverage = 31.3.", "GnomAD exomes allele count = 1 is less than 5 for AD gene KRAS, good gnomAD exomes coverage = 59.5." ], "strength": "Supporting" } ], "gene_id": 12340, "sample_findings": { "phenotypes": "No matching phenotype found for gene KRAS which is associated with Acute Myeloid Leukemia, Arteriovenous Malformations of the Brain, Autoimmune Lymphoproliferative Syndrome Type 4, Cardiofaciocutaneous Syndrome, and 17 more, according to CGD, ClinGen Disease Validity, GenCC, Mondo, and gene2phenotype.", "mode_of_inheritance": "AD, based on gene information from CGD, ClinGen Disease Validity, GenCC, Mondo, and gene2phenotype." } }, "amp_annotation": { "version_name": "13.14.0", "verdict": { "tier": "Tier I", "approx_score": 3.345 }, "classifications": [ { "name": "Crtd", "tier": "Tier I", "user_explain": { "Tier I": [ "Bowel Cancer, Erdheim-Chester Disease, Langerhans Cell Histiocytosis, Myeloid Cancer, and 7 more, 8 therapies (Cobimetinib, Trametinib, ASP3082, Daraxonrasib, and 4 more), sensitive, actionable, diagnostic, and resistant, FDA or Standard Care, Clinical Evidence, curated, and FDA-approved, from OncoKB, citing %%PUBMED:40644648%%, %%PUBMED:38593348%%, %%PUBMED:32991018%%, %%PUBMED:30867592%%, and 16 more. No patient information was provided to match the cancer." ], "Tier II": [ "All Solid Tumors, Bowel Cancer, Lung Cancer, Ovary/Fallopian Tube, and Pancreas Cancer, 9 therapies (Cetuximab, Dactolisib + Selumetinib, ASP3082, Binimetinib, and 5 more), actionable, prognostic, and diagnostic, curated, Clinical Evidence, pre-clinical, and case reports, from CIViC and OncoKB, citing %%PUBMED:36472553%%, %%PUBMED:33933896%%, %%PUBMED:27959684%%, %%PUBMED:27010960%%, and 10 more. No patient information was provided to match the cancer." ], "Tier III": [ "Bowel Cancer, Lung Cancer, Hairy Cell Leukemia, Melanoma, and 2 more, 8 therapies (Vemurafenib, Akt Inhibitor Mk2206, Cetuximab + Panitumumab, Dabrafenib, and 4 more), actionable, case reports, pre-clinical, and Clinical Evidence, from CIViC, citing %%PUBMED:26352686%%, %%PUBMED:26161928%%, %%PUBMED:24265155%%, %%PUBMED:23524406%%, and 7 more. No patient information was provided to match the cancer.", "Variant not found in CKB." ] }, "approx_score": 9.0 }, { "name": "Drug", "tier": "Tier I", "user_explain": { "Tier I": [ "8 therapies (Cobimetinib, Trametinib, ASP3082, Daraxonrasib, and 4 more), Sensitive, Actionable, Diagnostic, and Resistant, FDA or Standard Care, Clinical Evidence, curated, and FDA-approved, from OncoKB. Citing %%PUBMED:40644648%%, %%PUBMED:38593348%%, %%PUBMED:32991018%%, %%PUBMED:30867592%%, and 16 more. Related to Bowel Cancer, Erdheim-Chester Disease, Langerhans Cell Histiocytosis, Myeloid Cancer, and 7 more. No patient information was provided to match the cancer." ], "Tier II": [ "9 therapies (Cetuximab, Dactolisib + Selumetinib, ASP3082, Binimetinib, and 5 more), Actionable, Prognostic, and Diagnostic, curated, Clinical Evidence, pre-clinical, and case reports, from CIViC and OncoKB. Citing %%PUBMED:36472553%%, %%PUBMED:33933896%%, %%PUBMED:27959684%%, %%PUBMED:27010960%%, and 10 more. Related to All Solid Tumors, Bowel Cancer, Lung Cancer, Ovary/Fallopian Tube, and Pancreas Cancer. No patient information was provided to match the cancer." ], "Tier III": [ "Searches for drugs or clinical trials are disabled because there is Tier I curated drug evidence for this variant.", "8 therapies (Vemurafenib, Akt Inhibitor Mk2206, Cetuximab + Panitumumab, Dabrafenib, and 4 more), Actionable, case reports, pre-clinical, and Clinical Evidence, from CIViC. Citing %%PUBMED:26352686%%, %%PUBMED:26161928%%, %%PUBMED:24265155%%, %%PUBMED:23524406%%, and 7 more. Related to Bowel Cancer, Lung Cancer, Hairy Cell Leukemia, Melanoma, and 2 more. No patient information was provided to match the cancer." ] }, "approx_score": 8.0 }, { "name": "Germ", "tier": "Tier I", "user_explain": { "Tier I": [ "This missense variant is classified Pathogenic by the germline classifier, using rules PS3_Very Strong, PM1, PM5, PP5_Moderate, and PM2_Supporting." ] }, "approx_score": 7.0 }, { "name": "Path", "tier": "Tier II", "user_explain": { "Tier II": [ "GHR reports that the KRAS gene provides instructions for making a protein called K-Ras that is part of a signaling pathway known as the RAS/MAPK pathway. Also, associates KRAS with the following 5 cancers: Autoimmune Lymphoproliferative Syndrome, Cholangiocarcinoma, Lung, Myeloid, and Nevus, Epidermal.", "Mondo associates gene KRAS with the following 14 cancers: Acute Myeloid Leukemia, Arteriovenous Malformations of the Brain, Autoimmune Lymphoproliferative Syndrome Type 4, Differentiated Thyroid Carcinoma, Encephalocraniocutaneous Lipomatosis, and 9 more.", "The Human Protein Atlas classifies KRAS as an oncogene." ] }, "approx_score": 6.0 }, { "name": "Pubs", "tier": "Tier I", "user_explain": { "Tier I": [ "VarSome users have linked 22 articles stating the variant is pathogenic (%%PUBMED:40619266%%, %%PUBMED:39501138%%, %%PUBMED:36523988%%, %%PUBMED:36414681%%, %%PUBMED:35075146%%, and 17 more) (4 by VarSome curation team)(4 entries have been automatically lifted over from hg38)." ] }, "approx_score": 5.0 }, { "name": "Soma", "tier": "Tier I", "user_explain": { "Tier I": [ "This variant is reported in 5 962 out of the 18 372 somatic samples for gene KRAS, which has 802 reported somatic variants. Its GnomAD ƒ = 0.00000401. This is statistically rated Tier I." ], "Tier III": [ "CBioPortal reports 5 006 samples, cancer type = 1 373 x Pancreatic Cancer, 1 250 x Colorectal Cancer, 717 x Non-Small Cell Lung Cancer, and 46 more, sample type = 2 816 x Primary, 1 253 x Metastasis, 29 x Primary Tumor, and 6 more, tissue = 1 690 x Bowel, 1 546 x Pancreas, 723 x Lung, and 26 more, citing 55 articles (%%PUBMED:30463544%%, %%PUBMED:29721857%%, %%PUBMED:29525983%%, %%PUBMED:29298116%%, %%PUBMED:27872090%%, and 50 more).", "CancerHotspots reports 758 samples, bio-type = 1 x protein_coding, cancer type = 324 x Pancreatic Cancer, 178 x Colorectal Cancer, 85 x Non-Small Cell Lung Cancer, and 25 more, tissue site = 324 x Pancreas, 213 x Bowel, 86 x Lung, and 22 more.", "GDC reports 198 samples, drugs = 20 x Oxaliplatin, 18 x Gemcitabine, 15 x Fluorouracil, and 47 more, outcomes = 96 x Disease Free and 70 x Recurred, sex = 101 x Male and 97 x Female, tissues = 63 x Bowel, 45 x Pancreas, 32 x Endometrioid endometrial adenocarcinoma, and 14 more.", "Variant not found in ICGC." ] }, "total_samples": 5962, "approx_score": 4.0 }, { "name": "Freq", "tier": "Tier II", "user_explain": { "Tier II": [ "Variant not found in gnomAD genomes, good gnomAD genomes coverage = 31.3.\nGnomAD exomes allele count = 1 is less than 5 for AD gene KRAS, good gnomAD exomes coverage = 59.5." ] }, "approx_score": 3.0 }, { "name": "Type", "tier": "Tier III", "user_explain": { "Tier III": [ "No relevant information.", "Variant is not predicted splicing: no prediction from MaxEntScan." ] }, "approx_score": 2.0 }, { "name": "Pred", "tier": "Tier III", "user_explain": { "Tier III": [ "No relevant information." ] }, "approx_score": 1.0 } ] }, "cbio_portal": [ { "version": "06-Jun-2023", "total_samples": 5006, "sample_id": null, "sample_type": [ { "key": "Primary", "value": 2816 }, { "key": "Metastasis", "value": 1253 }, { "key": "Primary Tumor", "value": 29 }, { "key": "Metastatic", "value": 26 }, { "key": "Recurrent", "value": 4 }, { "key": "Local Recurrence", "value": 3 }, { "key": "Met", "value": 2 }, { "key": "Cell Line", "value": 1 }, { "key": "Recurrence", "value": 1 } ], "study_name": null, "mutation_status": [ { "key": "Somatic", "value": 3019 }, { "key": "Somatic_Vs_Pool", "value": 1 } ], "validation_status": [ { "key": "Valid", "value": 190 }, { "key": "Untested", "value": 63 }, { "key": "High", "value": 33 }, { "key": "Not_Done", "value": 9 }, { "key": "Validated", "value": 9 }, { "key": "__Unknown__,Valid,Valid", "value": 1 } ], "center": [ { "key": "Mskcc", "value": 2502 }, { "key": "Broad.Mit.Edu", "value": 211 }, { "key": "Qcmg.Uq.Edu.Au", "value": 160 }, { "key": "Genome.Wustl.Edu", "value": 70 }, { "key": "Dfci.Harvard.Edu", "value": 45 }, { "key": "Hgsc.Bcm.Edu", "value": 41 }, { "key": "Ut Southwestern", "value": 37 }, { "key": "Baylor College Of Medicine", "value": 29 }, { "key": "Papaemmanuil_Nejm_2016", "value": 19 }, { "key": "Mskcc-Cmo", "value": 17 }, { "key": "Target", "value": 12 }, { "key": "Msk-Impact468", "value": 10 }, { "key": "Msk-Impact410", "value": 10 }, { "key": "Genentech", "value": 9 }, { "key": "Ohsu.Edu", "value": 9 }, { "key": "University Of Michigan", "value": 8 }, { "key": "Http://Www.Wuxiapptec.Com", "value": 7 }, { "key": "Oicr.On.Ca", "value": 7 }, { "key": "Mskcc.Org", "value": 7 }, { "key": "Omrf.Org", "value": 6 }, { "key": "Msk-Impact410+Idtcustom_18_20161108", "value": 6 }, { "key": "Msk-Impact410+Kinghamt20150127Spikein", "value": 4 }, { "key": "Foundation", "value": 4 }, { "key": "Msk-Impact341+Kinghamt20150127Spikein", "value": 3 }, { "key": "Msk-Impact", "value": 3 }, { "key": "Papaemmanuil_Mds_2013", "value": 3 }, { "key": "John Hopkins", "value": 3 }, { "key": "Metabric", "value": 2 }, { "key": "Nccs", "value": 2 }, { "key": "Mdanderson.Org/Ucsc.Edu/Broad.Mit.Edu", "value": 2 }, { "key": "Wcm", "value": 2 }, { "key": "Pfizer_Uhongkong", "value": 2 }, { "key": "St. Jude Children'S Research Hospital", "value": 2 }, { "key": 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"value": 6 }, { "key": "Appendiceal Adenocarcinoma", "value": 6 }, { "key": "Cholangiocarcinoma", "value": 5 }, { "key": "Esophageal Adenocarcinoma", "value": 5 }, { "key": "Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor", "value": 4 }, { "key": "Mucinous Ovarian Cancer", "value": 4 }, { "key": "Cervical Squamous Cell Carcinoma", "value": 4 }, { "key": "Plasma Cell Myeloma", "value": 3 }, { "key": "Cutaneous Melanoma", "value": 3 }, { "key": "Extrahepatic Cholangiocarcinoma", "value": 3 }, { "key": "Papillary Renal Cell Carcinoma", "value": 3 }, { "key": "Adenosquamous Carcinoma of the Pancreas", "value": 3 }, { "key": "Pancreatobiliary Ampullary Carcinoma", "value": 3 }, { "key": "Ampullary Carcinoma", "value": 2 }, { "key": "High-Grade Neuroendocrine Carcinoma of the Colon and Rectum", "value": 2 }, { "key": "Acute Myeloid Leukemia", "value": 2 }, { "key": "Large Cell Neuroendocrine Carcinoma", "value": 2 }, { "key": "Intrahepatic Cholangiocarcinoma", "value": 2 }, { "key": "Seminoma", "value": 2 }, { "key": "Glioblastoma Multiforme", "value": 2 }, { "key": "Upper Tract Urothelial Carcinoma", "value": 2 }, { "key": "Sarcomatoid Carcinoma of the Urinary Bladder", "value": 1 }, { "key": "Rhabdomyosarcoma", "value": 1 }, { "key": "Serous Borderline Ovarian Tumor", "value": 1 }, { "key": "Small Cell Lung Cancer", "value": 1 }, { "key": "Low-Grade Serous Ovarian Cancer", "value": 1 }, { "key": "Thymoma", "value": 1 }, { "key": "Prostate Adenocarcinoma", "value": 1 }, { "key": "Unclassified Renal Cell Carcinoma", "value": 1 }, { "key": "Perihilar Cholangiocarcinoma", "value": 1 }, { "key": "Uterine Mixed Endometrial Carcinoma", "value": 1 }, { "key": "Urethral Adenocarcinoma", "value": 1 }, { "key": "Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma", "value": 1 }, { "key": "High-Grade Glioma, NOS", "value": 1 }, { "key": "Adenocarcinoma of the Gastroesophageal Junction", "value": 1 }, { "key": "Anaplastic Oligodendroglioma", "value": 1 }, { "key": "Bladder Adenocarcinoma", "value": 1 }, { "key": "Breast Invasive Ductal Carcinoma", "value": 1 }, { "key": "Clear Cell Ovarian Cancer", "value": 1 }, { "key": "Endocervical Adenocarcinoma", "value": 1 }, { "key": "Ewing Sarcoma", "value": 1 }, { "key": "Gastrointestinal Neuroendocrine Tumors", "value": 1 }, { "key": "Goblet Cell Adenocarcinoma of the Appendix", "value": 1 }, { "key": "Hepatocellular Carcinoma", "value": 1 }, { "key": "Oral Cavity Squamous Cell Carcinoma", "value": 1 }, { "key": "Inflammatory Myofibroblastic Tumor", "value": 1 }, { "key": "Intraductal Papillary Mucinous Neoplasm", "value": 1 }, { "key": "Invasive Breast Carcinoma", "value": 1 }, { "key": "Larynx Squamous Cell Carcinoma", "value": 1 }, { "key": "Melanoma of Unknown Primary", "value": 1 }, { "key": "Mucinous Cystic Neoplasm", "value": 1 }, { "key": "Mucosal Melanoma of the Vulva/Vagina", "value": 1 }, { "key": "Myelodysplastic Syndromes", "value": 1 }, { "key": "Non-Small Cell Lung Cancer", "value": 1 } ], "cancer_type": [ { "key": "Pancreatic Cancer", "value": 324 }, { "key": "Colorectal Cancer", "value": 178 }, { "key": "Non-Small Cell Lung Cancer", "value": 85 }, { "key": "Endometrial Cancer", "value": 30 }, { "key": "Appendiceal Cancer", "value": 25 }, { "key": "Esophagogastric Cancer", "value": 22 }, { "key": "Bladder Cancer", "value": 14 }, { "key": "Hepatobiliary Cancer", "value": 12 }, { "key": "Small Bowel Cancer", "value": 7 }, { "key": "Ovarian Cancer", "value": 7 }, { "key": "Cancer of Unknown Primary", "value": 6 }, { "key": "Ampullary Cancer", "value": 5 }, { "key": "Melanoma", "value": 5 }, { "key": "Cervical Cancer", "value": 5 }, { "key": "Glioma", "value": 4 }, { "key": "Renal Cell Carcinoma", "value": 4 }, { "key": "Mature B-Cell Neoplasms", "value": 3 }, { "key": "Gastrointestinal Neuroendocrine Tumor", "value": 3 }, { "key": "Germ Cell Tumor", "value": 2 }, { "key": "Head and Neck Cancer", "value": 2 }, { "key": "Leukemia", "value": 2 }, { "key": "Breast Cancer", "value": 2 }, { "key": "Soft Tissue Sarcoma", "value": 2 }, { "key": "Small Cell Lung Cancer", "value": 1 }, { "key": "Thymic Tumor", "value": 1 }, { "key": "Prostate Cancer", "value": 1 }, { "key": "Bone Cancer", "value": 1 }, { "key": "Myelodysplastic Syndromes", "value": 1 } ], "tissue_type": [ { "key": "Pancreas", "value": 324 }, { "key": "Bowel", "value": 213 }, { "key": "Lung", "value": 86 }, { "key": "Uterus", "value": 30 }, { "key": "Esophagus/Stomach", "value": 22 }, { "key": "Bladder/Urinary Tract", "value": 14 }, { "key": "Biliary Tract", "value": 11 }, { "key": "Ovary/Fallopian Tube", "value": 7 }, { "key": "Other", "value": 6 }, { "key": "Cervix", "value": 5 }, { "key": "Ampulla of Vater", "value": 5 }, { "key": "CNS/Brain", "value": 4 }, { "key": "Skin", "value": 4 }, { "key": "Kidney", "value": 4 }, { "key": "Lymphoid", "value": 3 }, { "key": "Myeloid", "value": 3 }, { "key": "Breast", "value": 2 }, { "key": "Soft Tissue", "value": 2 }, { "key": "Testis", "value": 2 }, { "key": "Head and Neck", "value": 2 }, { "key": "Liver", "value": 1 }, { "key": "Bone", "value": 1 }, { "key": "Prostate", "value": 1 }, { "key": "Thymus", "value": 1 }, { "key": "Vulva/Vagina", "value": 1 } ] } ], "phylop100way": [ { "version": "13-Apr-2021", "conservation_score": [ "7.746" ] } ], "maxentscan": null, "oncokb": [ { "version": "v5.4", "allele_exist": true, "diagnostic_implications": [ { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "", "level_of_evidence": "LEVEL_Dx2", "pmids": [ "22934674", "23512829" ], "tumor_type": { "children": {}, "code": "MDS", "color": "LightSalmon", "id": 505, "level": 3, "main_type": { "id": null, "name": "Myelodysplastic Syndromes", "tumor_form": "LIQUID" }, "name": "Myelodysplastic Syndromes", "parent": "MNM", "tissue": "Myeloid", "tumor_form": "LIQUID" } }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "", "level_of_evidence": "LEVEL_Dx2", "pmids": [ "10049057", "23832011", "25691160", "26457647", "12717436" ], "tumor_type": { "children": {}, "code": "JMML", "color": "LightSalmon", "id": 813, "level": 4, "main_type": { "id": null, "name": "Myelodysplastic/Myeloproliferative Neoplasms", "tumor_form": "LIQUID" }, "name": "Juvenile Myelomonocytic Leukemia", "parent": "MDS/MPN", "tissue": "Myeloid", "tumor_form": "LIQUID" } }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "", "level_of_evidence": "LEVEL_Dx3", "pmids": [ "22237106" ], "tumor_type": { "children": {}, "code": "ETPLL", "color": "LimeGreen", "id": 757, "level": 4, "main_type": { "id": null, "name": "T-Lymphoblastic Leukemia/Lymphoma", "tumor_form": "LIQUID" }, "name": "Early T-Cell Precursor Lymphoblastic Leukemia", "parent": "TLL", "tissue": "Lymphoid", "tumor_form": "LIQUID" } } ], "diagnostic_summary": "", "gene_exist": true, "gene_summary": "KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal and pancreatic cancers.", "highest_diagnostic_implication_level": "LEVEL_Dx2", "highest_fda_level": "LEVEL_Fda2", "highest_prognostic_implication_level": null, "highest_resistance_level": "LEVEL_R1", "highest_sensitive_level": "LEVEL_1", "hotspot": true, "last_update": "05/13/2025", "mutation_effect": { "citations": { "abstracts": [ { "abstract": "Nagashima et al. Abstract# 5735, AACR 2023.", "link": "https://aacrjournals.org/cancerres/article/83/7_Supplement/5735/722276" } ], "pmids": [ "17349581", "19296721", "11751631", "15093544", "30341394", "28572459", "20570890", "32792368", "20147967" ] }, "description": "The KRAS G12D mutation is located in the P-loop of the catalytic G-domain of the protein. This mutation has been found in lung, colorectal, pancreatic and ovarian cancer (PMID: 28572459). Expression of this mutation in cell lines and mouse models demonstrated that it is activating, as measured by increased downstream pathway activation, colony formation and in vivo tumor development across multiple lineages compared to wildtype (PMID: 20570890, 20147967, 11751631, 15093544,19296721,17349581, 32792368). In vitro studies have demonstrated that this mutation confers resistance to BRAF inhibition in lymphoid cells as measured by decreased pathway activation in the presence of the drug, but is sensitive to the MEK inhibitor cobimetinib (PMID: 30341394). A patient with hairy cell leukemia acquired a KRAS G12D mutation following relapse on the BRAF inhibitor vemurafenib but was successfully treated with the cobimetinib for at least twelve months (PMID: 30341394). Preclinical studies with xenograft mouse models expressing KRAS G12D demonstrated sensitivity to treatment with ASP3082 as measured by reduced tumor volume following treatment (Abstract: Nagashima et al. Abstract# 5735, AACR 2023. https://aacrjournals.org/cancerres/article/83/7_Supplement/5735/722276)", "knowneffect": "Gain-of-function" }, "oncogenic": "Oncogenic", "other_significant_resistance_levels": null, "other_significant_sensitive_levels": null, "prognostic_implications": null, "prognostic_summary": "", "query": { "canonicaltranscript": null, "id": null, "referencegenome": "GRCh37", "hugosymbol": "KRAS", "entrezgeneid": 3845, "alterationtype": null, "svtype": null, "alteration": "G12D", "tumortype": null, "proteinend": null, "consequence": null, "hgvs": null, "hgvsinfo": null, "proteinstart": null }, "treatments": [ { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Cetuximab and panitumumab are anti-EGFR monoclonal antibodies that are FDA-approved for patients with EGFR expressing, RAS-wildtype colorectal cancer. Patients with metastatic colorectal cancer (mCRC) harboring either exon 2 (e.g. G12, G13) or non-exon 2 (e.g Q61, K117, A146) KRAS mutations do not respond favorably to the anti-EGFR therapies cetuximab (PMID: 21228335, 20619739) or panitumumab (PMID: 18316791, 20921465, 24024839).", "approved_indications": [], "drugs": [ { "drug_name": "Cetuximab", "ncit_code": "C1723" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_R1", "level_associated_cancer_type": { "children": {}, "code": "", "color": "SaddleBrown", "id": 40, "level": 0, "main_type": { "id": null, "name": "Colorectal Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Bowel", "tumor_form": "SOLID" }, "pmids": [ "20921465", "21228335", "20619739", "24024839", "18316791" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Tucatinib, a small molecular inhibitor of HER2, and trastuzumab, a HER2-targeted antibody, are FDA-approved in combination for the treatment of patients with HER2 amplified metastatic colorectal cancer whose tumors are also RAS and BRAF wildtype. Patients with metastatic colorectal cancer harboring KRAS mutations do not respond favorably to trastuzumab as seen in the MyPath trial. In the multiple basket MyPath Phase IIa trial of pertuzumab and trastuzumab in which 56 metastatic colorectal cancer patients with HER2 amplification received combination therapy, the objective response rate for patients with KRAS wildtype colorectal cancer (43/56 patients) compared to KRAS mutated colorectal cancer (13/56 patients) was 40% (17/43, 95% CI, 25%–56%) versus 8% (1/13, 95% CI 0.2%–36%), respectively (PMID: 30857956).", "approved_indications": [], "drugs": [ { "drug_name": "Tucatinib", "ncit_code": "C77896" }, { "drug_name": "Trastuzumab", "ncit_code": "C1647" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_R1", "level_associated_cancer_type": { "children": {}, "code": "", "color": "SaddleBrown", "id": 40, "level": 0, "main_type": { "id": null, "name": "Colorectal Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Bowel", "tumor_form": "SOLID" }, "pmids": [ "30857956" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Cetuximab and panitumumab are anti-EGFR monoclonal antibodies that are FDA-approved for patients with EGFR expressing, RAS-wildtype colorectal cancer. Patients with metastatic colorectal cancer (mCRC) harboring either exon 2 (e.g. G12, G13) or non-exon 2 (e.g Q61, K117, A146) KRAS mutations do not respond favorably to the anti-EGFR therapies cetuximab (PMID: 21228335, 20619739) or panitumumab (PMID: 18316791, 20921465, 24024839).", "approved_indications": [], "drugs": [ { "drug_name": "Panitumumab", "ncit_code": "C1857" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_R1", "level_associated_cancer_type": { "children": {}, "code": "", "color": "SaddleBrown", "id": 40, "level": 0, "main_type": { "id": null, "name": "Colorectal Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Bowel", "tumor_form": "SOLID" }, "pmids": [ "20921465", "21228335", "20619739", "24024839", "18316791" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Avutometinib, a RAF/MEK clamp inhibitor, and defactinib, a FAK inhibitor, are FDA-approved in combination for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. FDA approval was based on the results of the Phase II RAMP-201 (NCT04625270) trial of avutometinib plus defactinib in 109 patients with recurrent LGSOC.\nIn the Phase II RAMP-201 (NCT04625270) trial, patients with KRAS-mutated LGSOC (n=57) demonstrated an overall response rate (ORR) of 44% (n=25), with a 2% (n=2) complete response (CR) rate, 40% (n=23) partial response (PR) rate and 49% (n=28) stable disease (SD) rate, a median duration of response (DOR) of 31.0 months (95% CI=14.8-31.1) and a median progression-free survival (PFS) of 22.0 months (95% CI=11.1-36.6) (PMID: 40644648). Responders included patients with the following KRAS mutations: KRAS A146V, G12D, G12R, G12V and Q61H (PMID: 40644648). Of patients with KRAS wildtype LGSOC (n=52), the cohort demonstrated an ORR of 17% (n=9), with a 17% (n=9) PR rate and 65% (n=34) SD rate, and a median PFS of 9.2 months (95% CI=5.5-NE) (PMID: 40644648).", "approved_indications": [], "drugs": [ { "drug_name": "Avutometinib", "ncit_code": "C80060" }, { "drug_name": "Defactinib", "ncit_code": "C79809" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "LGSOC", "color": "LightBlue", "id": 796, "level": 4, "main_type": { "id": null, "name": "Ovarian Cancer", "tumor_form": "SOLID" }, "name": "Low-Grade Serous Ovarian Cancer", "parent": "SOC", "tissue": "Ovary/Fallopian Tube", "tumor_form": "SOLID" }, "pmids": [ "40644648" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib and cobimetinib are MEK1/2 kinase inhibitors that are FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations and are NCCN-listed for patients with Erdheim-Chester Disease (ECD). In an open-label, phase II trial (NCT02649972) of cobimetinib in eighteen adult patients with histiocytoses of any mutational status (n = 12/18 patients with ECD, n = 1/12 patients with KRAS R149G, n = 1/12 patients with KRAS G12R), the overall response rate was 89% (90% CI= 73–100), 100% of responses were ongoing at one year, and 94% of patients remained progression-free (PMID: 30867592).", "approved_indications": [], "drugs": [ { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "ECD", "color": "LightSalmon", "id": 854, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Erdheim-Chester Disease", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "30867592" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib and cobimetinib are MEK1/2 kinase inhibitors that are FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations and are NCCN-listed for patients with Langerhans Cell Histiocytosis (LCH). In an open-label, phase II trial (NCT02649972) of cobimetinib in eighteen adult patients with histiocytoses of any mutational status (n = 2/18 patients with LCH, n = 1/2 patients with KRAS G13C), the overall response rate was 89% (90% CI= 73–100), 100% of responses were ongoing at one year, and 94% of patients remained progression-free (PMID: 30867592). In a study of three patients with LCH who were treated with trametinib, two patients harbored BRAF N486_P490del mutations, of which one had no reactivation and the other had a partial response, and the third patient with a MEK1 K57_G61del mutation had a complete response with no active disease after 22 months (PMID: 32991018).", "approved_indications": [], "drugs": [ { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "LCH", "color": "LightSalmon", "id": 792, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Langerhans Cell Histiocytosis", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "32991018", "30867592" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib and cobimetinib are MEK1/2 kinase inhibitors that are FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations and are NCCN-listed for patients with Rosai-Dorfman Disease. One adult patient with Rosai-Dorfman Disease with an activating KRAS G12R mutation was treated with cobimetinib and a follow-up CT scan two months after treatment showed a substantial response (PMID: 29236635).", "approved_indications": [], "drugs": [ { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "RDD", "color": "LightSalmon", "id": 855, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Rosai-Dorfman Disease", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "29236635" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib and cobimetinib are MEK1/2 kinase inhibitors that are FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations and are NCCN-listed for patients with Erdheim-Chester Disease (ECD). In an open-label, phase II trial (NCT02649972) of cobimetinib in eighteen adult patients with histiocytoses of any mutational status (n = 12/18 patients with ECD, n = 1/12 patients with KRAS R149G, n = 1/12 patients with KRAS G12R), the overall response rate was 89% (90% CI= 73–100), 100% of responses were ongoing at one year, and 94% of patients remained progression-free (PMID: 30867592).", "approved_indications": [], "drugs": [ { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "ECD", "color": "LightSalmon", "id": 854, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Erdheim-Chester Disease", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "30867592" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib and cobimetinib are MEK1/2 kinase inhibitors that are FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations and are NCCN-listed for patients with Langerhans Cell Histiocytosis (LCH). In an open-label, phase II trial (NCT02649972) of cobimetinib in eighteen adult patients with histiocytoses of any mutational status (n = 2/18 patients with LCH, n = 1/2 patients with KRAS G13C), the overall response rate was 89% (90% CI= 73–100), 100% of responses were ongoing at one year, and 94% of patients remained progression-free (PMID: 30867592). In a study of three patients with LCH who were treated with trametinib, two patients harbored BRAF N486_P490del mutations, of which one had no reactivation and the other had a partial response, and the third patient with a MEK1 K57_G61del mutation had a complete response with no active disease after 22 months (PMID: 32991018).", "approved_indications": [], "drugs": [ { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "LCH", "color": "LightSalmon", "id": 792, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Langerhans Cell Histiocytosis", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "32991018", "30867592" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib and cobimetinib are MEK1/2 kinase inhibitors that are FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations and are NCCN-listed for patients with Rosai-Dorfman Disease. One adult patient with Rosai-Dorfman Disease with an activating KRAS G12R mutation was treated with cobimetinib and a follow-up CT scan two months after treatment showed a substantial response (PMID: 29236635).", "approved_indications": [], "drugs": [ { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "RDD", "color": "LightSalmon", "id": 855, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Rosai-Dorfman Disease", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "29236635" ] }, { "abstracts": [ { "abstract": "Nagashima et al. Abstract# 5735, AACR 2023.", "link": "https://aacrjournals.org/cancerres/article/83/7_Supplement/5735/722276" }, { "abstract": "Park, W. et al., Abstract# 608O, ESMO 2024.", "link": "https://www.annalsofoncology.org/article/S0923-7534(24)02194-X/fulltext" } ], "alterations": [ "G12D" ], "description": "ASP3082 is an intravenously administered, small molecule KRAS G12D-targeted degrader. There are promising clinical data of response to ASP3082 in patients with KRAS G12D-mutant non-small cell lung cancer (NSCLC). In the Phase I (NCT05382559) trial of ASP3082 in thirteen patients with KRAS G12D-mutant NSCLC, the overall response rate was 23.1%, with three partial responses and eight stable disease responses, and the disease control rate was 84.6% (Abstract: Park, W. et al., Abstract# 608O, ESMO 2024. https://www.annalsofoncology.org/article/S0923-7534(24)02194-X/fulltext) In vivo studies with KRAS G12D-mutant NSCLC mouse xenograft models demonstrated antitumor activity to ASP3082 as measured by tumor regression (Abstract: Nagashima et al. Abstract# 5735, AACR 2023. https://aacrjournals.org/cancerres/article/83/7_Supplement/5735/722276)", "approved_indications": [], "drugs": [ { "drug_name": "ASP3082", "ncit_code": "C191205" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_3A", "level_associated_cancer_type": { "children": {}, "code": "", "color": "Gainsboro", "id": 102, "level": 0, "main_type": { "id": null, "name": "Non-Small Cell Lung Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Lung", "tumor_form": "SOLID" }, "pmids": [] }, { "abstracts": [ { "abstract": "Nagashima et al. Abstract# 5735, AACR 2023.", "link": "https://aacrjournals.org/cancerres/article/83/7_Supplement/5735/722276" }, { "abstract": "Park, W. et al., Abstract# 608O, ESMO 2024.", "link": "https://www.annalsofoncology.org/article/S0923-7534(24)02194-X/fulltext" } ], "alterations": [ "G12D" ], "description": "ASP3082 is an intravenously administered, small molecule KRAS G12D-targeted degrader. There are promising clinical data of response to ASP3082 in patients with KRAS G12D-mutated pancreatic ductal adenocarcinoma (PDAC). In the Phase I (NCT05382559) trial of ASP3082 in 27 patients with KRAS G12D-mutant PDAC, the overall response rate was 18.5%, with five partial responses and eight stable disease responses, and the disease control rate was 48.1% (Abstract: Park, W. et al., Abstract# 608O, ESMO 2024. https://www.annalsofoncology.org/article/S0923-7534(24)02194-X/fulltext) In vivo studies with KRAS G12D-mutant PDAC mouse xenograft models demonstrated antitumor activity to ASP3082 as measured by tumor regression (Abstract: Nagashima et al. Abstract# 5735, AACR 2023. https://aacrjournals.org/cancerres/article/83/7_Supplement/5735/722276)", "approved_indications": [], "drugs": [ { "drug_name": "ASP3082", "ncit_code": "C191205" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_3A", "level_associated_cancer_type": { "children": {}, "code": "PAAD", "color": "Purple", "id": 225, "level": 2, "main_type": { "id": null, "name": "Pancreatic Cancer", "tumor_form": "SOLID" }, "name": "Pancreatic Adenocarcinoma", "parent": "PANCREAS", "tissue": "Pancreas", "tumor_form": "SOLID" }, "pmids": [] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib and cobimetinib are MEK1/2 kinase inhibitors that are FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations and are NCCN-listed for patients with histiocytic neoplasms harboring MAPK pathway mutations. In a Phase II trial of cobimetinib in eighteen patients with histiocytoses, the overall response rate was 89%, with 13/18 patients (72%) having a complete response and 15/18 patients harboring a MAPK pathway mutation (PMID: 30867592). All three patients harboring KRAS mutations had a partial or complete response to treatment with cobimetinib (PMID: 30867592). Small case studies have also demonstrated the clinical efficacy of MEK inhibition in patients with histiocytic neoplasms (PMID: 29236635). In a case study of one eighteen-year-old patient with refractory histiocytic sarcoma harboring a pathogenic variant of MAP2K1 (F53L), the patient was treated with trametinib and showed an excellent response prior to treatment interruption due to severe adverse events (PMID: 30361829).", "approved_indications": [], "drugs": [ { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_3A", "level_associated_cancer_type": { "children": {}, "code": "", "color": "LightSalmon", "id": 29, "level": 0, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "", "parent": null, "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "30361829", "29236635", "30867592" ] }, { "abstracts": [ { "abstract": "Koltun et al. Abstract# 3597, AACR 2022.", "link": "https://aacrjournals.org/cancerres/article/82/12_Supplement/3597/702320" }, { "abstract": "Arbour, KC. et al., Abstract#6520, Annals of Oncol., 2023.", "link": "https://www.annalsofoncology.org/article/S0923-7534%2823%2902675-3/fulltext" }, { "abstract": "Singh et al. Abstract # 3597, AACR 2022.", "link": "https://s3.us-west-2.amazonaws.com/rvmdpubs.revmed.com/2022/AACR_2022_Singh.pdf" } ], "alterations": [ "G12R", "G12A", "G12D", "G12S", "G12V" ], "description": "Daraxonrasib is an orally available, small-molecule RAS(ON) multi-selective noncovalent inhibitor. There are promising clinical data in patients with non-small cell lung cancer (NSCLC) harboring a KRAS G12 mutation treated with daraxonrasib. \nIn a clinical study of daraxonrasib in 39 patients with KRAS G12X-mutant NSCLC (n=3 KRAS G12A, n=17 KRAS G12D, n=17 KRAS G12V, n=2 KRAS G12S), the overall response rate was 38% (15/39), with one patient (3%) demonstrating complete response (n=1 KRAS G12V), fourteen patients (35%) demonstrating partial response (n=7 KRAS G12D, n=7 KRAS G12V), nineteen patients (48%) demonstrating stable disease (n=1 KRAS G12A, n=8 KRAS G12D, n=9 KRAS G12V, n=1 KRAS G12S) and five patients (13%) demonstrating progressive disease (n=2 KRAS G12A, n=2 KRAS G12D, n=1 KRAS G12S) (Abstract: Arbour, KC. et al., Abstract#6520, Annals of Oncol., 2023. https://www.annalsofoncology.org/article/S0923-7534%2823%2902675-3/fulltext) In a case report, a patient with NSCLC harboring KRAS G12V was treated with daraxonrasib and achieved a complete response with a 100% decrease in both target lesions (PMID: 38593348). In vitro studies with KRAS position 12 (G12X) mutated RAS-addicted cell lines demonstrated increased sensitivity to daraxonrasib as measured by increased inhibition of cellular proliferation compared to other RAS-mutated cell lines (Abstract: Singh et al. Abstract # 3597, AACR 2022. https://s3.us-west-2.amazonaws.com/rvmdpubs.revmed.com/2022/AACR_2022_Singh.pdf) In vivo human xenograft models with KRAS G12X mutant tumors demonstrated sensitivity to daraxonrasib as measured by dose-dependent tumor regression, anti-tumor immunity and RAS pathway inhibition (Abstract: Koltun et al. Abstract# 3597, AACR 2022. https://aacrjournals.org/cancerres/article/82/12_Supplement/3597/702320)", "approved_indications": [], "drugs": [ { "drug_name": "Daraxonrasib", "ncit_code": "C188048" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_3A", "level_associated_cancer_type": { "children": {}, "code": "", "color": "Gainsboro", "id": 102, "level": 0, "main_type": { "id": null, "name": "Non-Small Cell Lung Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Lung", "tumor_form": "SOLID" }, "pmids": [ "38593348" ] }, { "abstracts": [ { "abstract": "Garrido-Laguna et al. 2025 ASCO Gastrointestinal Cancers Symposium.", "link": "https://www.asco.org/abstracts-presentations/ABSTRACT474560" }, { "abstract": "Arbour et al. Abstract# 6520, Annals of Oncol., 2023.", "link": "https://www.annalsofoncology.org/article/S0923-7534%2823%2902675-3/fulltext" } ], "alterations": [ "G12R", "G12A", "G12D", "G12S", "G12V" ], "description": "Daraxonrasib is an orally available, small-molecule RAS(ON) multi-selective noncovalent inhibitor. There are promising clinical data in patients with pancreatic adenocarcinoma harboring a KRAS G12 mutation treated with daraxonrasib. \nIn the Phase I RMC-6236-001 (NCT05379985) trial of daraxonrasib in 127 patients with RAS-mutant pancreatic adenocarcinoma (PDAC), the KRAS G12X-mutant cohort (n=42) demonstrated a median progression-free survival (PFS) of 8.5 months (95% CI=5.3-11.7), an objective response rate (ORR) of 29% (95% CI=16–45) and a median overall survival (OS) of 14.5 months (95% CI=8.8-NE) (Abstract: Garrido-Laguna et al. 2025 ASCO Gastrointestinal Cancers Symposium. https://www.asco.org/abstracts-presentations/ABSTRACT474560) Of the RAS-mutant cohort (G12X, G13X or Q61X) (n=57), the median PFS was 7.6 months (95% CI=5.9-11.1), the ORR was 25% (95% CI=14-38) and the median OS was 14.5 months (95% CI=8.8-NE) (Abstract: Garrido-Laguna et al. 2025 ASCO Gastrointestinal Cancers Symposium. https://www.asco.org/abstracts-presentations/ABSTRACT474560) In a clinical study of daraxonrasib in 44 patients with KRAS G12X-mutant pancreatic adenocarcinoma (n=23 KRAS G12D, n=9 KRAS G12V, n=11 KRAS G12R, n=1 KRAS G12S), the overall response rate was 20% (9/44), with nine patients (20%) demonstrating partial response (n=4 KRAS G12D, n=2 KRAS G12V, n=3 KRAS G12R), 32 patients (73%) demonstrating stable disease (n=17 KRAS G12D, n=6 KRAS G12V, n=8 KRAS G12R, n=1 KRAS G12S) and two patients (4.5%) demonstrating progressive disease (n=2 KRAS G12D) (Abstract: Arbour et al. Abstract# 6520, Annals of Oncol., 2023. https://www.annalsofoncology.org/article/S0923-7534%2823%2902675-3/fulltext) \nPreclinical studies with KRAS G12X mutated RAS-addicted cell lines and KRAS G12X mutant human xenograft models demonstrated increased sensitivity to daraxonrasib as measured by increased inhibition of cellular proliferation, dose-dependent tumor regression, anti-tumor immunity and RAS pathway inhibition (PMID: 38593348).", "approved_indications": [], "drugs": [ { "drug_name": "Daraxonrasib", "ncit_code": "C188048" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_3A", "level_associated_cancer_type": { "children": {}, "code": "PAAD", "color": "Purple", "id": 225, "level": 2, "main_type": { "id": null, "name": "Pancreatic Cancer", "tumor_form": "SOLID" }, "name": "Pancreatic Adenocarcinoma", "parent": "PANCREAS", "tissue": "Pancreas", "tumor_form": "SOLID" }, "pmids": [ "38593348" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib and cobimetinib are MEK1/2 kinase inhibitors that are FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations and are NCCN-listed for patients with histiocytic neoplasms harboring MAPK pathway mutations. In a Phase II trial of cobimetinib in eighteen patients with histiocytoses, the overall response rate was 89%, with 13/18 patients (72%) having a complete response and 15/18 patients harboring a MAPK pathway mutation (PMID: 30867592). All three patients harboring KRAS mutations had a partial or complete response to treatment with cobimetinib (PMID: 30867592). Small case studies have also demonstrated the clinical efficacy of MEK inhibition in patients with histiocytic neoplasms (PMID: 29236635). In a case study of one eighteen-year-old patient with refractory histiocytic sarcoma harboring a pathogenic variant of MAP2K1 (F53L), the patient was treated with trametinib and showed an excellent response prior to treatment interruption due to severe adverse events (PMID: 30361829).", "approved_indications": [], "drugs": [ { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_3A", "level_associated_cancer_type": { "children": {}, "code": "", "color": "LightSalmon", "id": 29, "level": 0, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "", "parent": null, "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "30361829", "29236635", "30867592" ] }, { "abstracts": [ { "abstract": "Nagashima et al. Abstract# 5735, AACR 2023.", "link": "https://aacrjournals.org/cancerres/article/83/7_Supplement/5735/722276" } ], "alterations": [ "G12D" ], "description": "ASP3082 is an intravenously administered, small molecule KRAS G12D degrader. There are promising laboratory data to support use of ASP3082 in patients with KRAS G12D-mutated solid tumors. In vitro studies with KRAS G12D-mutated pancreatic cancer cells demonstrated selective sensitivity to ASP3082 as measured by degradation of KRAS G12D, inhibition of ERK phosphorylation and inhibition of cellular proliferation compared to KRAS wildtype cancer cells (Abstract: Nagashima et al. Abstract# 5735, AACR 2023. https://aacrjournals.org/cancerres/article/83/7_Supplement/5735/722276) In vivo studies with KRAS G12D-mutant pancreatic ductal adenocarcinoma and non-small cell lung cancer mouse xenograft models demonstrated antitumor activity to ASP3082 as measured by tumor regression (Abstract: Nagashima et al. Abstract# 5735, AACR 2023. https://aacrjournals.org/cancerres/article/83/7_Supplement/5735/722276)", "approved_indications": [], "drugs": [ { "drug_name": "ASP3082", "ncit_code": "C191205" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_4", "level_associated_cancer_type": { "children": {}, "code": "", "color": "", "id": 5, "level": -1, "main_type": { "id": null, "name": "All Solid Tumors", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "", "tumor_form": "SOLID" }, "pmids": [] }, { "abstracts": [ { "abstract": "Koltun et al. Abstract# 3597, AACR 2022.", "link": "https://aacrjournals.org/cancerres/article/82/12_Supplement/3597/702320" }, { "abstract": "Singh et al. Abstract # 3597, AACR 2022.", "link": "https://s3.us-west-2.amazonaws.com/rvmdpubs.revmed.com/2022/AACR_2022_Singh.pdf" } ], "alterations": [ "G12R", "G12A", "G12D", "G12S", "G12V" ], "description": "Daraxonrasib is an orally available, small-molecular inhibitor of RAS. In vitro studies in human RAS-addicted cancer cell lines demonstrated sensitivity to daraxonrasib as measured by decreased ERK phosphorylation, decreased cell growth and induced apoptosis (Abstract: Koltun et al. Abstract# 3597, AACR 2022. https://aacrjournals.org/cancerres/article/82/12_Supplement/3597/702320) In vitro studies with KRAS position 12 (G12X) mutated RAS-addicted cell lines demonstrated increased sensitivity to daraxonrasib as measured by increased inhibition of cellular proliferation compared to other RAS-mutated cell lines (Abstract: Singh et al. Abstract # 3597, AACR 2022. https://s3.us-west-2.amazonaws.com/rvmdpubs.revmed.com/2022/AACR_2022_Singh.pdf) In vivo human xenograft models with KRAS G12X mutant tumors demonstrated sensitivity to daraxonrasib as measured by dose-dependent tumor regression, anti-tumor immunity and RAS pathway inhibition (Abstract: Koltun et al. Abstract# 3597, AACR 2022. https://aacrjournals.org/cancerres/article/82/12_Supplement/3597/702320) In a mouse clinical trial of daraxonrasib with KRAS G12X-mutant models of non-small cell lung cancer (n=15), pancreatic ductal adenocarcinoma (n=18) and colorectal cancer (n=18), the objective response rate was 53% (8/15), 61% (11/18) and 44% (8/18), respectively (Abstract: Singh et al. Abstract # 3597, AACR 2022. https://s3.us-west-2.amazonaws.com/rvmdpubs.revmed.com/2022/AACR_2022_Singh.pdf)", "approved_indications": [], "drugs": [ { "drug_name": "Daraxonrasib", "ncit_code": "C188048" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_4", "level_associated_cancer_type": { "children": {}, "code": "", "color": "", "id": 5, "level": -1, "main_type": { "id": null, "name": "All Solid Tumors", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "", "tumor_form": "SOLID" }, "pmids": [] }, { "abstracts": [], "alterations": [ "G12D" ], "description": "MRTX-1133 is an orally available, small-molecule inhibitor of KRAS G12D. In vitro studies with KRAS G12D-mutant PDAC cell lines demonstrated selective sensitivity to MRTX-1133 as measured by inhibition of KRAS G12D and downstream MAPK signaling activity compared to KRAS wildtype and KRAS G12C-mutant cell lines (PMID: 36472553). In vivo studies with KRAS G12D-mutant pancreatic ductal adenocarcinoma mouse xenograft models demonstrated antitumor activity to MRTX-1133 as measured by complete or near-complete remissions following treatment (PMID: 36472553).", "approved_indications": [], "drugs": [ { "drug_name": "MRTX-1133", "ncit_code": "C200319" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_4", "level_associated_cancer_type": { "children": {}, "code": "", "color": "", "id": 5, "level": -1, "main_type": { "id": null, "name": "All Solid Tumors", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "", "tumor_form": "SOLID" }, "pmids": [ "36472553" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib, cobimetinib, and binimetinib are MEK1/2 kinase inhibitors that are NCCN-listed and FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. In a multicenter, single-arm, open-label, phase IB trial (NCT02964689) of binimetinib in combination with cisplatin and pemetrexed in fourteen evaluable patients with stage III-IV NSCLC with KRAS (codon 12, 13 or 61) mutations, the overall response rate was 33% (95% CI=7–70) among the nine patients that received binimetinib, where three of nine patients had a partial response, two of nine had stable disease, three of nine had progressive disease, and one of nine was not assessable for response (PMID: 33933896). On average, in vitro studies have shown that trametinib inhibits the proliferation of KRAS mutant cancer cell lines (n = 50) with lower IC50s than other MEK inhibitors, including selumetinib (PMID: 24746704). Cobimetinib, which inhibits the kinase activity of MEK but allows the induction of RAF-dependent feedback phosphorylation of MEK, was demonstrated to be less effective in KRAS-mutant tumors than in BRAF-mutant tumors (PMID: 25435214, 23934108).", "approved_indications": [], "drugs": [ { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_4", "level_associated_cancer_type": { "children": {}, "code": "", "color": "", "id": 5, "level": -1, "main_type": { "id": null, "name": "All Solid Tumors", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "", "tumor_form": "SOLID" }, "pmids": [ "33933896", "25435214", "24746704", "23934108" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib, cobimetinib, and binimetinib are MEK1/2 kinase inhibitors that are NCCN-listed and FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. In a multicenter, single-arm, open-label, phase IB trial (NCT02964689) of binimetinib in combination with cisplatin and pemetrexed in fourteen evaluable patients with stage III-IV NSCLC with KRAS (codon 12, 13 or 61) mutations, the overall response rate was 33% (95% CI=7–70) among the nine patients that received binimetinib, where three of nine patients had a partial response, two of nine had stable disease, three of nine had progressive disease, and one of nine was not assessable for response (PMID: 33933896). On average, in vitro studies have shown that trametinib inhibits the proliferation of KRAS mutant cancer cell lines (n = 50) with lower IC50s than other MEK inhibitors, including selumetinib (PMID: 24746704). Cobimetinib, which inhibits the kinase activity of MEK but allows the induction of RAF-dependent feedback phosphorylation of MEK, was demonstrated to be less effective in KRAS-mutant tumors than in BRAF-mutant tumors (PMID: 25435214, 23934108).", "approved_indications": [], "drugs": [ { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_4", "level_associated_cancer_type": { "children": {}, "code": "", "color": "", "id": 5, "level": -1, "main_type": { "id": null, "name": "All Solid Tumors", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "", "tumor_form": "SOLID" }, "pmids": [ "33933896", "25435214", "24746704", "23934108" ] }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "Trametinib, cobimetinib, and binimetinib are MEK1/2 kinase inhibitors that are NCCN-listed and FDA-approved for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. In a multicenter, single-arm, open-label, phase IB trial (NCT02964689) of binimetinib in combination with cisplatin and pemetrexed in fourteen evaluable patients with stage III-IV NSCLC with KRAS (codon 12, 13 or 61) mutations, the overall response rate was 33% (95% CI=7–70) among the nine patients that received binimetinib, where three of nine patients had a partial response, two of nine had stable disease, three of nine had progressive disease, and one of nine was not assessable for response (PMID: 33933896). On average, in vitro studies have shown that trametinib inhibits the proliferation of KRAS mutant cancer cell lines (n = 50) with lower IC50s than other MEK inhibitors, including selumetinib (PMID: 24746704). Cobimetinib, which inhibits the kinase activity of MEK but allows the induction of RAF-dependent feedback phosphorylation of MEK, was demonstrated to be less effective in KRAS-mutant tumors than in BRAF-mutant tumors (PMID: 25435214, 23934108).", "approved_indications": [], "drugs": [ { "drug_name": "Binimetinib", "ncit_code": "C84865" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_4", "level_associated_cancer_type": { "children": {}, "code": "", "color": "", "id": 5, "level": -1, "main_type": { "id": null, "name": "All Solid Tumors", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "", "tumor_form": "SOLID" }, "pmids": [ "33933896", "25435214", "24746704", "23934108" ] } ], "tumor_type_summary": "", "variant_exist": true, "variant_summary": "The KRAS G12D mutation is known to be oncogenic.", "variant_id": null, "vus": false } ] }