Variant Annotation
Available parameters and response documentation is available here
GET /lookup/KRAS:G12D?add-AMP-annotation=1
{ "chromosome": "chr12", "alt": "T", "ref": "C", "pos": 25398284, "variant_id": "10190120253982840004", "regions": { "uniprot_regions": { "version": "04-Oct-2024", "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": "v8", "items": [ { "GTExJsonData": { "exon_id": "ENSG00000133703.11_2", "exon_number": "2", "expressions": { "adipose_subcutaneous": 0.24816700000000003, "adipose_visceral_omentum": 0.233175, "adrenal_gland": 0.146678, "artery_aorta": 0.16673900000000005, 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0.27291800000000005, "esophagus_gastroesophageal_junction": 0.23684200000000002, "esophagus_mucosa": 0.436691, "esophagus_muscularis": 0.28041400000000005, "fallopian_tube": 0.12909800000000002, "heart_atrial_appendage": 0.11550900000000001, "heart_left_ventricle": 0.07862380000000002, "kidney_cortex": 0.11378300000000002, "kidney_medulla": 0.12651, "liver": 0.0793788, "lung": 0.260569, "minor_salivary_gland": 0.28472800000000004, "muscle_skeletal": 0.126186, "nerve_tibial": 0.293141, "ovary": 0.12246500000000002, "pancreas": 0.10574800000000001, "pituitary": 0.08660480000000002, "prostate": 0.124353, "skin_not_sun_exposed_suprapubic": 0.22044900000000006, "skin_sun_exposed_lower_leg": 0.23953800000000003, "small_intestine_terminal_ileum": 0.24460700000000002, "spleen": 0.11971500000000003, "stomach": 0.21645800000000004, "testis": 0.22627300000000003, "thyroid": 0.16103400000000004, "uterus": 0.16544400000000006, "vagina": 0.25765699999999997, "whole_blood": 0.28084600000000004 }, "gencode_id": "ENSG00000133703", "gene": "KRAS", "gene_model_positions": { "chromosome": "chr12", "end": 25403870, "start": 25358070, "strand": "-" }, "gene_positions": { "chromosome": "chr12", "end": 25403870, "start": 25357723, "strand": "-" } }, "absolute_positon": 545230195, "chromo": "chr12", "length": 121, "position": 25398209 } ] } }, "variant_type": "SNV", "cytobands": "12p12.1", "refseq_transcripts": [ { "items": [ { "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": true, "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_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": false, "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_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": "224" } ], "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 } ], 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"list_s2_score": [ 0.557244, 0.333767, 0.331367, 0.333767 ], "list_s2_rankscore": 0.19380000233650208, "bayesdel_addaf_pred": [ "D" ], "bayesdel_addaf_score": 0.39786601066589355, "bayesdel_addaf_rankscore": 0.8979099988937378, "bayesdel_noaf_pred": [ "D" ], "bayesdel_noaf_score": 0.333730012178421, "bayesdel_noaf_rankscore": 0.8966299891471863, "metarnn_pred": [ "D", "D", "D", "D" ], "metarnn_score": [ 0.897719, 0.897719, 0.897719, 0.897719 ], "metarnn_rankscore": 0.8912799954414368, "m_cap_pred": [ "D" ], "m_cap_score": 0.1646459996700287, "m_cap_rankscore": 0.8437100052833557, "dann_score": 0.9977665543556213, "dann_rankscore": 0.864329993724823 } ], "dann_snvs": [ { "version": "2014", "dann_score": 0.9977568895535142 } ], "ncbi_clinvar2": [ { "version": "08-Nov-2024", "review_status": "criteria provided, multiple submitters, no conflicts", "review_stars": 2, "variation_id": 12582, "num_submitters": 22, "pub_med_references": [ 2278970, 3122217, 7773929, 8439212, 12460918, 12720172, 15093544, 15696205, 15842656, 16361624, 16434492, 16618717, 17332249, 17384584, 17704260, 17910045, 18316791, 18794081, 19018267, 19029981, 19047918, 19075190, 19114683, 19255327, 19358724, 19679400, 19773371, 20805368, 20921462, 20921465, 20949522, 21079152, 21228335, 21975775, 22025163, 22407852, 22499344, 22683711, 23014527, 23096712, 23255105, 23406027, 25044103, 25157968, 25695684, 29298116, 30443000, 30936194, 31836588, 31891627, 35794233 ], "clinical_significance": [ "Likely Pathogenic", "Pathogenic" ], "last_evaluation": "20241103", "origin": null, "accessions": [ { "variation_id": 12582, "accession_id": "RCV000585796", "review_status": "criteria provided, single submitter", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20180314, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Cerebral arteriovenous malformation", "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" ] } ], "pub_med_references": [ 29298116 ], "review_stars": 1, "review_date": 20231103, "submission_description": [], "variant_id": 10190120253982840004, "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, "origin": "somatic", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "108010" } } ], "date_updated": 20231224, "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 ], "origin": "somatic", "method": "literature only", "diseases": [ { "normalized_disease": [ "Arteriovenous Malformations of the Brain" ], "normalized_cancer": [ "CNS/Brain" ], "names": [ "Arteriovenous Malformations of the Brain" ] } ], "date_updated": 20180314, "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": 20191216, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000992585" } ] }, { "variation_id": 12582, "accession_id": "RCV000272938", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20161206, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND not provided", "diseases": [ { "symbols": { "medgen": "C3661900" }, "names": [ "Not Provided", "None Provided" ] } ], "review_date": 20221222, "review_stars": 2, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "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, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20221231, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000329383" }, { "submitter_date": 20241010, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "CeGaT Center for Human Genetics Tuebingen", "review_date": 20221201, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "CN517202" } } ], "date_updated": 20241020, "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", "origin": "unknown", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20221129, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001550138" } ] }, { "variation_id": 12582, "accession_id": "RCV000548006", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20171226, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND RASopathy", "diseases": [ { "normalized_disease": [ "Rasopathy" ], "symbols": { "medgen": "C5555857", "mondo": "MONDO:0021060" }, "names": [ "Rasopathy", "Rasopathies", "Noonan Spectrum Disorder" ] } ], "review_date": 20221005, "review_stars": 2, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "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, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "CN166718" } } ], "date_updated": 20221119, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002601600" }, { "submitter_date": 20171005, "submission_description": [ "This sequence change replaces glycine with aspartic acid at codon 12 of the KRAS protein (p.Gly12Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs121913529, ExAC 0.01%). 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 nevus sebaceous syndrome (PMID: 23255105, 22683711, 23096712, 26521233). It was also observed in a child with epidermal nevus, polycystic kidneys, rhabdomyosarcoma and growth retardation (PMID: 20805368). In one family this variant was found in an infant with severe Schimmelpenning syndrome, whereas the monozygotic twin brother was unaffected showing that this variant in the affected individual was due to a postzygotic somatic event (PMID: 22683711, 23255105). ClinVar contains an entry for this variant (Variation ID: 12582). 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). Experimental studies using mouse knock-in models have shown that this missense change results in the activation of KRAS and increase in proliferation of mouse embryonic cells. In addition, pancreatic tissue from mice expressing this variant show de-differentiation and activation of signaling factors that initiate pancreatic cancer (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": 20170630, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "CN166718" } } ], "date_updated": 20171226, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000659085" } ] }, { "variation_id": 12582, "accession_id": "RCV004018620", "review_status": "criteria provided, single submitter", "allele_id": 27621, "review_description": "Likely pathogenic", "clinical_significance": [ "Likely pathogenic" ], "date_created": 20240501, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Cardiovascular phenotype", "diseases": [ { "symbols": { "medgen": "CN230736" }, "names": [ "Cardiovascular Phenotype" ] } ], "review_date": 20220822, "review_stars": 1, "submission_description": [], "variant_id": 10190120253982840004, "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, "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "medgen": "CN230736" } } ], "date_updated": 20240501, "clinical_significance": [ "Likely pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005023563" } ] }, { "variation_id": 12582, "accession_id": "RCV004554600", "review_status": "criteria provided, single submitter", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20240519, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Congenital Pulmonary Airway Malformations", "diseases": [ { "names": [ "Congenital Pulmonary Airway Malformations" ] } ], "review_date": 20220719, "review_stars": 1, "submission_description": [], "variant_id": 10190120253982840004, "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, "origin": "de novo", "method": "clinical testing", "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" ] } ], "date_updated": 20240519, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005044128" } ] }, { "variation_id": 12582, "accession_id": "RCV000029215", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20130404, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Linear nevus sebaceous syndrome", "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", "Sfm Syndrome", "Jadassohn Nevus Phakomatosis", "Linear Nevus Sebaceous Syndrome", "Organoid Nevus Phakomatosis", "Linear Nevus Sebaceous Syndrome", "Sebaceous Nevus Syndrome Hemimegalencephaly", "Linear Nevus Sebaceous Syndrome", "Linear Nevus Sebaceous Syndrome", "Linear Sebaceous Nevus Sequence" ] } ], "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "review_stars": 2, "review_date": 20220322, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20220325, "submission_description": [ "Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012582). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012583,VCV000012584, PMID:17704260). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.875>=0.6, 3CNET: 0.995>=0.75). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline." ], "review_description": "Pathogenic", "submitter_name": "3billion", "review_date": 20220322, "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0000618" }, "normalized_phenotype": [ "Blindness" ] }, { "symbols": { "hp": "HP:0002059" }, "normalized_phenotype": [ "Cerebral Atrophy" ] }, { "symbols": { "hp": "HP:0002007" }, "normalized_phenotype": [ "Frontal Bossing" ] }, { "symbols": { "hp": "HP:0002315" }, "normalized_phenotype": [ "Headache" ] }, { "symbols": { "hp": "HP:0002716" }, "normalized_phenotype": [ "Lymphadenopathy" ] }, { "symbols": { "hp": "HP:0010815" }, "normalized_phenotype": [ "Nevus Sebaceous" ] }, { "symbols": { "hp": "HP:0002650" }, "normalized_phenotype": [ "Scoliosis" ] } ], "diseases": [ { "symbols": { "omim": "163200" } } ], "date_updated": 20220402, "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 ], "origin": "somatic", "method": "literature only", "diseases": [ { "normalized_disease": [ "Linear Nevus Sebaceous Syndrome" ], "normalized_cancer": [ "SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC" ], "names": [ "Linear Nevus Sebaceous Syndrome" ] } ], "date_updated": 20220312, "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", "origin": "somatic", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "163200" } } ], "date_updated": 20210619, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001736991" } ] }, { "variation_id": 12582, "accession_id": "RCV001799604", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20220101, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Capillary malformation-arteriovenous malformation 1", "diseases": [ { "normalized_disease": [ "Capillary Malformation-Arteriovenous Malformation 1" ], "symbols": { "orphanet": "137667", "omim": "608354", "medgen": "C4747394", "mondo": "MONDO:0020783" }, "names": [ "Capillary Malformation-Arteriovenous Malformation 1" ] } ], "review_date": 20210501, "review_stars": 0, "submission_description": [], "variant_id": 10190120253982840004, "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" } ] }, { "variation_id": 12582, "accession_id": "RCV000856666", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20191129, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Primary low grade serous adenocarcinoma of ovary", "diseases": [ { "normalized_cancer": [ "Ovary/Fallopian Tube" ], "symbols": { "medgen": "C4302356" }, "names": [ "Primary Low Grade Serous Adenocarcinoma Ovary" ] } ], "review_date": 20191104, "review_stars": 0, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20191104, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "University Health Network, Princess Margaret Cancer Centre", "review_date": 20191104, "origin": "somatic", "method": "research", "diseases": [ { "normalized_cancer": [ "Ovary/Fallopian Tube" ], "symbols": { "medgen": "C4302356" }, "names": [ "Primary Low Grade Serous Adenocarcinoma Ovary" ] } ], "date_updated": 20191129, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000999192" } ] }, { "variation_id": 12582, "accession_id": "RCV000013411", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20130404, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Carcinoma of pancreas", "diseases": [ { "pub_med": [ 17060676, 24493721, 25394175 ], "normalized_disease": [ "Exocrine Pancreatic Carcinoma", "Familial Pancreatic Carcinoma" ], "symbols": { "orphanet": "1333", "medgen": "C0235974", "mesh": "C562463", "mondo": "MONDO:0005192" }, "names": [ "Exocrine Pancreatic Carcinoma", "Pancreatic Acinar Carcinoma", "Exocrine Pancreatic Carcinoma", "Familial Pancreatic Carcinoma", "Familial Pancreatic Carcinoma", "Exocrine Pancreatic Carcinoma" ], "normalized_cancer": [ "Pancreas" ], "disease_mechanism": "loss of function" } ], "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "review_stars": 0, "review_date": 20190207, "submission_description": [], "variant_id": 10190120253982840004, "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, "origin": "somatic", "method": "research", "finding": [ { "symbols": { "hp": "HP:0002894" }, "normalized_phenotype": [ "Neoplasm Of The Pancreas" ] } ], "diseases": [ { "symbols": { "omim": "260350" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000882700" }, { "submitter_date": 20160718, "submission_description": [], "review_description": "not provided", "submitter_name": "Database of Curated Mutations (DoCM)", "review_date": 20160310, "origin": "somatic", "method": "literature only", "diseases": [ { "symbols": { "mesh": "C562463" } } ], "date_updated": 20170308, "clinical_significance": [ "not provided" ], "review_status": "no assertion provided", "accession_id": "SCV000504487" }, { "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 ], "origin": "somatic", "method": "literature only", "diseases": [ { "normalized_disease": [ "Familial Pancreatic Carcinoma" ], "normalized_cancer": [ "Pancreas" ], "names": [ "Familial Pancreatic Carcinoma" ] } ], "date_updated": 20220312, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000033658" } ] }, { "variation_id": 12582, "accession_id": "RCV000433573", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic/Likely pathogenic", "clinical_significance": [ "Pathogenic", "Likely pathogenic" ], "date_created": 20170308, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Acute myeloid leukemia", "diseases": [ { "pub_med": [ 22138009, 23970018, 32171751 ], "normalized_disease": [ "Acute Myeloid Leukemia" ], "symbols": { "orphanet": "519", "omim": "601626", "medgen": "C0023467", "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", "Acute Myeloid Leukemia", "Leukemia, Acute Myelogenous, Somatic" ], "normalized_cancer": [ "Acute Myeloid Leukemia", "Acute myelogenous leukemia", "Acute non-lymphocytic leukemia", "Acute granulocytic leukemia", "Leukemia, acute myelogenous, somatic" ], "disease_mechanism": "Constitutively activated FLT3" } ], "review_date": 20180330, "review_stars": 0, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20210421, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Hematopathology, The University of Texas M.D. Anderson Cancer Center", "review_date": 20180330, "origin": "somatic", "method": "clinical testing", "diseases": [ { "normalized_disease": [ "Acute Myeloid Leukemia" ], "normalized_cancer": [ "Acute Myeloid Leukemia" ], "names": [ "Acute Myeloid Leukemia" ] } ], "date_updated": 20210424, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001571657" }, { "submitter_date": 20160718, "submission_description": [], "review_description": "Likely pathogenic", "submitter_name": "Database of Curated Mutations (DoCM)", "review_date": 20141002, "origin": "somatic", "method": "literature only", "diseases": [ { "symbols": { "mesh": "D015470" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000504482" } ] }, { "variation_id": 12582, "accession_id": "RCV000425250", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Likely pathogenic", "clinical_significance": [ "Likely pathogenic" ], "date_created": 20170308, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Lung carcinoma", "diseases": [ { "pub_med": [ 23562183, 24846033, 25311215, 24627688, 23667368, 29355391, 29398453, 30813707 ], "normalized_disease": [ "Lung Carcinoma" ], "normalized_cancer": [ "Lung" ], "symbols": { "medgen": "C0684249", "mondo": "MONDO:0005138" }, "names": [ "Lung Carcinoma" ], "keyword": "Hereditary cancer syndrome" } ], "review_date": 20160310, "review_stars": 0, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20160718, "submission_description": [], "review_description": "Likely pathogenic", "submitter_name": "Database of Curated Mutations (DoCM)", "review_date": 20160310, "origin": "somatic", "method": "literature only", "diseases": [ { "symbols": { "omim": "211980" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000504484" } ] }, { "variation_id": 12582, "accession_id": "RCV000150896", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20150130, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Non-small cell lung carcinoma", "diseases": [ { "pub_med": [ 24868098, 24673736, 24627688, 23667368, 30813707 ], "normalized_disease": [ "Non-Small Cell Lung Carcinoma" ], "symbols": { "medgen": "C0007131", "mesh": "D002289", "mondo": "MONDO:0005233", "human_phenotype_ontology": "HP:0030358" }, "names": [ "Non-Small Cell Lung Carcinoma", "Non-Small Cell Lung Carcinoma" ], "normalized_cancer": [ "Non-Small Cell Lung Cancer" ], "disease_mechanism": "Other" } ], "review_date": 20160310, "review_stars": 0, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20160718, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Database of Curated Mutations (DoCM)", "review_date": 20160310, "origin": "somatic", "method": "literature only", "diseases": [ { "symbols": { "mesh": "D002289" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000504486" }, { "submitter_date": 20160426, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine", "review_date": 20140828, "origin": "somatic", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0007131" } } ], "date_updated": 20160529, "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", "origin": "somatic", "method": "research", "diseases": [ { "symbols": { "hp": "HP:0030358" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000882686" } ] }, { "variation_id": 12582, "accession_id": "RCV000662266", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Likely pathogenic", "clinical_significance": [ "Likely pathogenic" ], "date_created": 20180714, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Vascular Tumors Including Pyogenic Granuloma", "diseases": [ { "normalized_cancer": [ "Vascular Tumors Including Pyogenic Granuloma" ], "names": [ "Vascular Tumors Including Pyogenic Granuloma" ] } ], "review_date": 20150219, "review_stars": 0, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20171127, "submission_description": [], "review_description": "Likely pathogenic", "submitter_name": "Yale Center for Mendelian Genomics, Yale University", "review_date": 20150219, "origin": "somatic", "method": "literature only", "diseases": [ { "normalized_cancer": [ "Vascular Tumors Including Pyogenic Granuloma" ], "names": [ "Vascular Tumors Including Pyogenic Granuloma" ] } ], "date_updated": 20180714, "clinical_significance": [ "Likely pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000784594" } ] }, { "variation_id": 12582, "accession_id": "RCV000426369", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20170308, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Neoplasm of the large intestine", "diseases": [ { "pub_med": [ 23012255 ], "normalized_disease": [ "Colorectal Neoplasm" ], "normalized_cancer": [ "Neoplasm of the large intestine", "Colorectal Neoplasms", "Colorectal neoplasm" ], "symbols": { "medgen": "C0009404", "mesh": "D015179", "mondo": "MONDO:0005335", "human_phenotype_ontology": "HP:0100834" }, "names": [ "Neoplasm Large Intestine", "Colorectal Neoplasms", "Colorectal Neoplasm" ] } ], "review_date": 20141002, "review_stars": 0, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20160718, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Database of Curated Mutations (DoCM)", "review_date": 20141002, "origin": "somatic", "method": "literature only", "diseases": [ { "symbols": { "mesh": "D015179" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000504481" } ] }, { "variation_id": 12582, "accession_id": "RCV000443973", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20170308, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Thyroid tumor", "diseases": [ { "normalized_disease": [ "Thyroid Tumor" ], "normalized_cancer": [ "Thyroid" ], "symbols": { "medgen": "C0040136", "mesh": "D013964", "mondo": "MONDO:0015074", "human_phenotype_ontology": "HP:0100031" }, "names": [ "Thyroid Tumor", "Thyroid Tumor" ] } ], "review_date": 20141002, "review_stars": 0, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20160718, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Database of Curated Mutations (DoCM)", "review_date": 20141002, "origin": "somatic", "method": "literature only", "diseases": [ { "symbols": { "mesh": "D013964" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000504483" } ] }, { "variation_id": 12582, "accession_id": "RCV000150897", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20150130, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Ovarian neoplasm", "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" ] } ], "review_date": 20141002, "review_stars": 0, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20160718, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Database of Curated Mutations (DoCM)", "review_date": 20141002, "origin": "somatic", "method": "literature only", "diseases": [ { "symbols": { "mesh": "D010051" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000504485" }, { "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, "origin": "somatic", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "167000" } } ], "date_updated": 20160529, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000198480" } ] }, { "variation_id": 12582, "accession_id": "RCV000144969", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20141122, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Juvenile myelomonocytic leukemia", "diseases": [ { "pub_med": [ 24493721 ], "normalized_disease": [ "Juvenile Myelomonocytic Leukemia" ], "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" ], "keyword": "Hereditary cancer syndrome" } ], "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "review_stars": 0, "review_date": 20140828, "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." ], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20160426, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine", "review_date": 20140828, "origin": "somatic", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "607785" } } ], "date_updated": 20160529, "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 ], "origin": "somatic", "method": "literature only", "diseases": [ { "normalized_disease": [ "Juvenile Myelomonocytic Leukemia" ], "normalized_cancer": [ "Juvenile Myelomonocytic Leukemia" ], "names": [ "Juvenile Myelomonocytic Leukemia" ] } ], "date_updated": 20220312, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000191996" } ] }, { "variation_id": 12582, "accession_id": "RCV000029214", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20130404, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Nevus sebaceous", "diseases": [ { "normalized_cancer": [ "NEVUS SEBACEOUS, SOMATIC" ], "symbols": { "medgen": "C3854181", "human_phenotype_ontology": "HP:0010815" }, "names": [ "Nevus Sebaceous", "Nevus Sebaceous, Somatic" ] } ], "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "review_stars": 0, "review_date": 20121025, "submission_description": [], "variant_id": 10190120253982840004, "submissions": [ { "submitter_date": 20171101, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Yale Center for Mendelian Genomics, Yale University", "review_date": 20121025, "origin": "somatic", "method": "literature only", "diseases": [ { "names": [ "Nevus Sebaceous" ] } ], "date_updated": 20151011, "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 ], "origin": "somatic", "method": "literature only", "diseases": [ { "normalized_cancer": [ "NEVUS SEBACEOUS, SOMATIC" ], "names": [ "Nevus Sebaceous, Somatic" ] } ], "date_updated": 20220312, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000051860" } ] }, { "variation_id": 12582, "accession_id": "RCV000144970", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20141122, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Autoimmune lymphoproliferative syndrome type 4", "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" ] } ], "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "review_stars": 0, "review_date": 20120610, "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." ], "variant_id": 10190120253982840004, "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 ], "origin": "somatic", "method": "literature only", "diseases": [ { "normalized_cancer": [ "RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC" ], "names": [ "Ras-Associated Autoimmune Leukoproliferative Disorder, Somatic" ] } ], "date_updated": 20220312, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000191997" } ] }, { "variation_id": 12582, "accession_id": "RCV002508117", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20230107, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Gastric cancer", "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" ] } ], "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "review_stars": 0, "review_date": 20120610, "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." ], "variant_id": 10190120253982840004, "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 ], "origin": "somatic", "method": "literature only", "diseases": [ { "normalized_disease": [ "Gastric Cancer" ], "normalized_cancer": [ "Esophagus/Stomach" ], "names": [ "Gastric Cancer" ] } ], "date_updated": 20220312, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000033659" } ] }, { "variation_id": 12582, "accession_id": "RCV000022799", "review_status": "no assertion criteria provided", "allele_id": 27621, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20130404, "title": "NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) AND Epidermal nevus", "diseases": [ { "normalized_disease": [ "Nevus, Epidermal" ], "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" ], "keyword": "Hereditary cancer syndrome" } ], "pub_med_references": [ 7773929, 8439212, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711 ], "review_stars": 0, "review_date": 20120610, "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." ], "variant_id": 10190120253982840004, "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. 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arteriovenous malformation ", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Congenital Pulmonary Airway Malformations", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "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": "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": "Juvenile myelomonocytic leukemia ", "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 carcinoma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Neoplasm of ovary", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Neoplasm of the large intestine", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "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": "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": "Thyroid tumor", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "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 myeloid 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 ] } ] } ], "weill_cornell_medicine_pmkb": [ { "version": "04-Oct-2024", "items": [ { "tier": 1, "definition": [ "KRAS G12A", "KRAS G12V", "KRAS G12D", "KRAS G12C", "KRAS G12S", "KRAS G12R", "KRAS G13C", "KRAS G13S", "KRAS G13R", "KRAS Q61H", "KRAS Q61L", "KRAS Q61K", "KRAS Q61R", "KRAS A146T", "KRAS A146V", "KRAS A146P", "KRAS A11V", "KRAS codon(s) 12, 13, 61, 117, 146 any" ], "interpretations": "KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. Such mutations are found in approximately 30% to 50% of metastatic colorectal tumors and are common in other tumor types. Mutations in the KRAS gene may indicate poor prognosis and poor drug response with therapies targeted to EGFR. The absence of a KRAS mutation predicts a greater likelihood of response to EGFR-targeted therapies and improved survival with such treatment. The relevant KRAS mutation is in one of five codons (12 13, 61, 117 or 146). The presence of KRAS mutations in codon 12, 13 or 61 is associated with a high likelihood of resistance to therapies targeting EGFR. In addition, mutations at codons 117 and 146 may also be associated with reduced response to EGFR-targeted therapies. Results should be interpreted in conjunction with other laboratory and clinical findings.\nDrug resistance: \nPanitumumab\nCetuximab", "tissues": [ "Colon", "Rectum" ], "tumour_types": [ "Adenocarcinoma", "Carcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "variants": [ "10190120253982840004", "10380120252453500004" ], "definition": "KRAS G12D", "type": "variantId", "gene_id": 12340 }, { "aa_positions": [ 12, 13, 61, 117, 146 ], "coding_impact": "any", "definition": "KRAS codon(s) 12, 13, 61, 117, 146 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 1, "definition": [ "KRAS codon(s) 12, 13, 61, 117, 146 any" ], "interpretations": "KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. Such mutations are found in approximately 30% to 60% of small intestine adenocarcinomas and are common in other tumor types. The relevant KRAS mutation is in one of five codons (12 13, 61, 117 or 146). KRAS mutations in small intestine tumors are associated with higher pT classification and more frequent pancreatic invasion. The effect of KRAS mutations on drug therapy has not been well established in the literature, however it has been extensively studied in colorectal adenocarcinoma. Mutations in the KRAS gene may indicate poor prognosis and poor drug response with therapies targeted to EGFR in colon cancer, and the absence of a KRAS mutation predicts a greater likelihood of response to EGFR-targeted therapies and improved survival with such treatment. The presence of KRAS mutations in codon 12, 13 or 61 is associated with a high likelihood of resistance to therapies targeting EGFR in colon cancer. In addition, mutations at codons 117 and 146 may also be associated with reduced response to EGFR-targeted therapies in colon cancer. Results should be interpreted in conjunction with other laboratory and clinical findings. ", "tissues": [ "Small Intestine" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "aa_positions": [ 12, 13, 61, 117, 146 ], "coding_impact": "any", "definition": "KRAS codon(s) 12, 13, 61, 117, 146 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS codon(s) 12, 13, 61, 117, 146 any" ], "interpretations": "KRAS is a well known proto-oncogene that belongs to the small GTPase family and functions as a central mediator of downstream growth factor receptor signaling, with a critical role for cell proliferation and survival. Pathogenic mutations in KRAS typically occur in codons 12-13 of exon 2 and codon 61 of exon 3; however, other, non-canonical, pathogenic mutations in KRAS have also been reported in acute myeoid leukemia. KRAS mutations have been described in approximately 3-15% of acute myeloid leukemia, 8-20% of chronic myelomonocytic leukemia, 14% of juvenile myelomonocytic leukemia, 8% of blastic plasmacytoid dendritic cell neoplasm 4% of patients with myelodysplastic syndrome, 2% of primary myelofibrosis, 12% of B cell acute lymphoblastic leukemia (often associated with MLL rearrangement) and 1-2% of T cell acute lymphoblastic leukemia. Investigation into the targetability of this pathway in leukemia has been attempted in some disease models.", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "Acute Myeloid Leukemia", "Chronic Myelomonocytic Leukemia", "Myelodysplastic Syndrome", "B Lymphoblastic Leukemia/Lymphoma", "T Lymphoblastic Leukemia/Lymphoma", "Acute Leukemia of Unspecified Cell Type", "Anemia", "Unspecified", "Atypical Chronic Myeloid Leukemia", "Chronic Myeloid Leukemia", "Chronic Neutrophilic Leukemia", "Cytopenia", "Eosinophilia", "Essential Thrombocythemia", "Histiocytic and Dendritic Cell Neoplasms", "Langerhans Cell Histiocytosis", "Leukocytosis", "Leukopenia", "Mast Cell Neoplasm", "MDS with Ring Sideroblasts", "Monocytosis", "Myelodysplastic/Myeloproliferative Neoplasm", "Myeloproliferative Neoplasm", "Myeloid Neoplasm", "Other Acute Leukemia", "Polycythemia Vera", "Polycythemia", "Primary Myelofibrosis", "Thrombocytopenia", "Thrombocytosis" ], "disease_or_trait": null, "pub_med_references": [ 16404744, 19075190, 23512829, 23690417, 23832011, 24072100, 24105326, 24150215, 24166518, 24220272, 24569456, 27385790 ], "variants": [ { "aa_positions": [ 12, 13, 61, 117, 146 ], "coding_impact": "any", "definition": "KRAS codon(s) 12, 13, 61, 117, 146 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS G12A", "KRAS G12V", "KRAS G12D", "KRAS G12C", "KRAS G12S", "KRAS G12R", "KRAS G13D", "KRAS G13C", "KRAS G13S", "KRAS G13R", "KRAS Q61H", "KRAS Q61L", "KRAS Q61K", "KRAS Q61R", "KRAS codon(s) 12, 13, 61, 117, 146 any" ], "interpretations": "KRAS belongs to the RAS family of oncogenes. In lung, KRAS mutations are detected in approximately 20% to 25% of adenocarcinoma and less than 10% of squamous cell carcinoma which demonstrate a minor glandular component. KRAS mutations in NSCLC most often occur in codons 12 or 13 and with a lower frequency in codon 61. Mutations in KRAS are usually mutually exclusive with other oncogenic driver aberrations including EGFR, BRAF, HER2 mutations and ALK and ROS1 rearrangements. Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at lower frequency in East Asian patient cohorts. The prognostic as well as predictive role of KRAS mutations continues to be studied. Although various attempts inhibiting KRAS have been made, there is no established therapy specific for this large patient subpopulation. Recommend correlation with other clinical and lab findings.", "tissues": [ "Lung" ], "tumour_types": [ "Squamous Cell Carcinoma" ], "disease_or_trait": null, "pub_med_references": [ 24158231, 26018876 ], "variants": [ { "coding_impact": "any", "variants": [ "10190120253982840004", "10380120252453500004" ], "definition": "KRAS G12D", "type": "variantId", "gene_id": 12340 }, { "aa_positions": [ 12, 13, 61, 117, 146 ], "coding_impact": "any", "definition": "KRAS codon(s) 12, 13, 61, 117, 146 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS G12A", "KRAS G12V", "KRAS G12D", "KRAS G12C", "KRAS G12S", "KRAS G12R", "KRAS G13D", "KRAS G13C", "KRAS G13S", "KRAS G13R", "KRAS Q61H", "KRAS Q61L", "KRAS Q61K", "KRAS Q61R", "KRAS codon(s) 12, 13, 61, 117, 146 any" ], "interpretations": "KRAS belongs to the RAS family of oncogenes. KRAS mutations are detected in approximately 20% to 25% of lung adenocarcinoma. Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at lower frequency in East Asian patient cohorts. Mutations in KRAS are usually mutually exclusive with other oncogenic driver aberrations including EGFR, BRAF, HER2 mutations and ALK and ROS1 rearrangements. KRAS mutations in NSCLC most often occur in codons 12 or 13 and with a lower frequency in codon 61. The prognostic as well as predictive role of KRAS mutations continues to be studied. Although various attempts inhibiting KRAS have been made, there is no established therapy specific for this large patient subpopulation.", "tissues": [ "Lung" ], "tumour_types": [ "Adenocarcinoma", "Pleomorphic Carcinoma", "Carcinoma", "Non-Small Cell Lung Carcinoma" ], "disease_or_trait": null, "pub_med_references": [ 26018876 ], "variants": [ { "coding_impact": "any", "variants": [ "10190120253982840004", "10380120252453500004" ], "definition": "KRAS G12D", "type": "variantId", "gene_id": 12340 }, { "aa_positions": [ 12, 13, 61, 117, 146 ], "coding_impact": "any", "definition": "KRAS codon(s) 12, 13, 61, 117, 146 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS G12A", "KRAS G12V", "KRAS G12D", "KRAS G12C", "KRAS G12S", "KRAS G12R", "KRAS G13D", "KRAS G13C", "KRAS G13S", "KRAS G13R", "KRAS Q61H", "KRAS Q61L", "KRAS Q61K", "KRAS Q61R", "KRAS A146T", "KRAS A146V", "KRAS A146P", "KRAS A11V", "KRAS codon(s) 12, 13, 61, 117, 146 any" ], "interpretations": "Pancreatic ductal adenocarcinoma (PDAC) is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. More than 90% of pancreatic ductal adenocarcinoma samples have a KRAS mutation which may have prognostic, and (with ongoing trials assessing the efficacy of novel KRAS inhibitors) possibly therapeutic implications. However, targeting KRAS directly has been difficult in these tumors.", "tissues": [ "Pancreas" ], "tumour_types": [ "Adenocarcinoma", "Carcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "variants": [ "10190120253982840004", "10380120252453500004" ], "definition": "KRAS G12D", "type": "variantId", "gene_id": 12340 }, { "aa_positions": [ 12, 13, 61, 117, 146 ], "coding_impact": "any", "definition": "KRAS codon(s) 12, 13, 61, 117, 146 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS G12D", "KRAS codon(s) 12 any" ], "interpretations": "KRAS belongs to the RAS family of oncogenes. KRAS mutations have been described in approximately 3-40% gall bladder adenocarcinomas (more often in East Asia). The prognostic and therapeutic implications of KRAS mutations in gall bladder adenocarcinomas continue to be explored.", "tissues": [ "Gall Bladder" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "variants": [ "10190120253982840004", "10380120252453500004" ], "definition": "KRAS G12D", "type": "variantId", "gene_id": 12340 }, { "aa_positions": [ 12 ], "coding_impact": "any", "definition": "KRAS codon(s) 12 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS codon(s) 12, 13, 61, 117, 146 any" ], "interpretations": "RAS mutations (HRAS, NRAS and KRAS) are found in all epithelial thyroid malignancies. The frequency of KRAS mutations in thyroid carcinomas is 2-3%. Overall, RAS mutations are identified in 10--20% of papillary carcinomas (follicular variant), 40--50% of follicular carcinomas and 20--40% of poorly differentiated and anaplastic carcinomas. Of note, RAS point mutations are mutually exclusive with other thyroid mutations such as BRAF, RET/PTC, or TRK rearrangements in papillary thyroid cancers. In follicular carcinomas, RAS mutations are mutually exclusive with PAX8-PPARG rearrangements. RAS mutations have also been associated with more aggressive disease and distant metastasis. The therapeutic implications of RAS mutations in thyroid cancer are unknown at this time.", "tissues": [ "Thyroid" ], "tumour_types": [ "Papillary Carcinoma", "Follicular Carcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "aa_positions": [ 12, 13, 61, 117, 146 ], "coding_impact": "any", "definition": "KRAS codon(s) 12, 13, 61, 117, 146 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS G12A", "KRAS G12V", "KRAS G12D", "KRAS G12S", "KRAS G12R" ], "interpretations": "KRAS mutations have been reported to be present in 16 to 41% of cases of low grade serous carcinoma of the ovary. The prognostic significance of KRAS mutations in ovarian tumors is uncertain; some reports suggest that patients with KRAS G12V may have shorter overall survival than patients without mutation, while other reports suggest that KRAS mutations in some low grade carcinomas of the ovary may be associated with slightly improved prognosis. In-vitro studies showed that cell lines with KRAS G12V mutation are more sensitive to selumetinib (MEK inhibitor) compared to cells with KRAS G12D. The clinical response to MEK inhibitors in patients with these tumors and mutations remains to be elucidated.", "tissues": [ "Ovary" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "variants": [ "10190120253982840004", "10380120252453500004" ], "definition": "KRAS G12D", "type": "variantId", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS codon(s) 12, 13, 61, 117, 146 any" ], "interpretations": "KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. KRAS mutations are frequent in low-grade mucinous tumors of appendiceal origin and pseudomyxoma peritonei (43-100%) where mutations commonly occur in codon 12 or 13, with G12D and G12V being the most common. However, appendiceal adenocarcinoma cases with goblet cell features usually lack KRAS mutations. Mutations in the KRAS gene may indicate poor prognosis and drug response with therapies targeted to EGFR in some settings. However, this should be interpreted in conjunction with other laboratory and clinical findings.", "tissues": [ "Appendix" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "aa_positions": [ 12, 13, 61, 117, 146 ], "coding_impact": "any", "definition": "KRAS codon(s) 12, 13, 61, 117, 146 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS codon(s) 12, 13, 61, 117, 146 any" ], "interpretations": "KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. KRAS mutations are common in both extrahepatic (40-49%) and intrahepatic (24-27%) cholangiocarcinomas. Mutations in the KRAS gene may indicate poor prognosis and drug response with therapies targeted to EGFR in some settings. Of note, RAS mutations sensitize tumors to MEK inhibitors. However, this should be interpreted in conjunction with other laboratory and clinical findings.", "tissues": [ "Ampulla (Pancreaticobiliary Duct)", "Liver" ], "tumour_types": [ "Adenocarcinoma", "Cholangiocarcinoma" ], "disease_or_trait": null, "pub_med_references": [ 26189129 ], "variants": [ { "aa_positions": [ 12, 13, 61, 117, 146 ], "coding_impact": "any", "definition": "KRAS codon(s) 12, 13, 61, 117, 146 any", "type": "codon", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS G12V", "KRAS G12D", "KRAS G12C", "KRAS G12S", "KRAS G12R", "KRAS G13D", "KRAS G13C", "KRAS G13S", "KRAS G13R", "KRAS G12A" ], "interpretations": "KRAS mutations are infrequent in gastric carcinomas and have been reported in approximately 6% of cases. Studies have shown no statistically significant difference in survival between KRAS-mutated and KRAS-non-mutated gastric carcinomas. However, one study showed a trend that the presence of a KRAS mutation was associated with better overall survival in gastric carcinoma patients. There is an increased frequency of KRAS mutations in gastric carcinomas with microsatellite instability. In gastric cancer, the predictive ability of KRAS has not been extensively studied, but a small study did not demonstrate an effect on survival in patients treated with an EGFR inhibitor.", "tissues": [ "Stomach" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "variants": [ "10190120253982840004", "10380120252453500004" ], "definition": "KRAS G12D", "type": "variantId", "gene_id": 12340 } ] }, { "tier": 2, "definition": [ "KRAS G12D" ], "interpretations": "KRAS, member of the RAS family of small GTPases which functions as an upstream regulator of the MAPK and PI3K pathways, is frequently mutated in a diverse range of cancers including pancreatic, colorectal and lung cancers. More than 90% of pancreatic ductal adenocarcinoma samples have a KRAS mutation which may have prognostic, and (with ongoing trials assessing the efficacy of novel KRAS inhibitors) possibly therapeutic implications. However, targeting KRAS directly has been difficult in these tumors. KRAS mutations are infrequent in gastric carcinomas and have been reported in approximately 6% of cases. The gain of function KRAS G12D mutation is known to be oncogenic.", "tissues": [ "Ampulla (Pancreaticobiliary Duct)" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "variants": [ "10190120253982840004", "10380120252453500004" ], "definition": "KRAS G12D", "type": "variantId", "gene_id": 12340 } ] } ] } ], "wustl_civic": [ { "version": "08-Dec-2023", "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/2247", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of patients receiving melphalan-based therapy, those with KRAS codon 12 mutations were less likely to have a positive response than those with wildtype KRAS (26.9% vs. 58.3%, P=0.015).", "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": [ 19284554 ], "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": "08-Dec-2023", "sex": [ { "key": "Female", "value": 61 }, { "key": "Male", "value": 53 } ], "age_freq": [ { "key": "60-70", "value": 36 }, { "key": "70-80", "value": 31 }, { "key": "50-60", "value": 25 }, { "key": "40-50", "value": 10 }, { "key": "80-90", "value": 10 }, { "key": "30-40", "value": 1 }, { "key": "90-100", "value": 1 } ], "os_status": [ { "key": "Living", "value": 102 }, { "key": "Deceased", "value": 12 } ], "race": [ { "key": "European (non-Finnish)", "value": 73 }, { "key": "African", "value": 11 }, { "key": "Latino", "value": 2 }, { "key": "Other", "value": 1 } ], "tumor_status": [ { "key": "Disease Free", "value": 65 }, { "key": "Recurred", "value": 38 } ], "tumor_tissue_site": null, "path_t_stage": [ { "key": "T3", "value": 54 }, { "key": "T2", "value": 9 }, { "key": "T4", "value": 7 }, { "key": "T1", "value": 5 }, { "key": "T4A", "value": 3 }, { "key": "T4B", "value": 3 }, { "key": "T1A", "value": 2 }, { "key": "T1B", "value": 2 }, { "key": "T1B1", "value": 1 }, { "key": "T1C", "value": 1 }, { "key": "T2B", "value": 1 } ], "path_n_stage": [ { "key": "N0", "value": 45 }, { "key": "N1", 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"gene_symbol": "KRAS", "hgvs": "G12D", "transcript": "NM_004985.5", "pub_med_references": [ 27123948 ], "pathogenicity": "P", "id": 3482, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 12, "gene_symbol": "KRAS", "hgvs": "G12D", "transcript": "NM_004985.5", "pub_med_references": [ 23497191 ], "pathogenicity": "P", "id": 23039, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr12:25245350 C⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 12, "gene_symbol": "KRAS", "hgvs": "G12D", "transcript": "NM_004985.5", "pub_med_references": [ 22247021 ], "pathogenicity": "P", "id": 23038, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr12:25245350 C⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 12, "gene_symbol": "KRAS", "hgvs": "G12D", "transcript": "NM_004985.5", "pub_med_references": [ 31649840 ], "pathogenicity": "DA", "id": 20045, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr12:25245350 C⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 12, "gene_symbol": "KRAS", "hgvs": "G12D", "transcript": "NM_004985.5", "pub_med_references": [ 32903495 ], "pathogenicity": "DA", "id": 20044, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr12:25245350 C⇒T" } ], "UNIPROT UniProt Variants": [ { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "UNIPROT UniProt Variants", "codon": 12, "gene_symbol": "KRAS", "hgvs": "G12D", "transcript": "NM_004985.5", "possible_functional_studies": [ 21079152, 29298116 ], "pub_med_references": [ 16533793, 17332249, 20805368, 20949522, 21079152, 22499344, 22683711, 29298116, 30891959, 34820593 ], "disease_name": [ "Acute myeloid leukemia", "Atypical endometrial hyperplasia", "Autoimmune lymphoproliferative syndrome type 4", "Capillary malformation-arteriovenous malformation 1", "Carcinoma of pancreas" ], "annotation_id": "VAR_016026" } ] } } ] } ], "acmg_annotation": { "version_name": "12.6.2", "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": 5.271, "pathogenic_score": 21, "pathogenic_subscore": "Pathogenic", "total_score": 21, "verdict": "Pathogenic" }, "classifications": [ "PS3_Very Strong", "PM1_Strong", "PM5_Strong", "PP3_Moderate", "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 Nov '24, 39 submissions of which 3 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:31891627%%, %%PUBMED:31836588%%, %%PUBMED:30936194%%, %%PUBMED:30443000%% 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)." ], "strength": "Very Strong" }, { "name": "PM1", "met_criteria": true, "user_explain": [ "Hot-spot of length 17 amino-acids has 52 missense/in-frame variants (32 pathogenic variants, 20 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 (26 pathogenic variants, 11 uncertain variants and no benign), which qualifies as moderate pathogenic." ], "strength": "Strong" }, { "name": "PM5", "met_criteria": true, "user_explain": [ "Alternative variant ##chr12:25398285 C⇒T## (Gly12Ser) is classified Pathogenic by UniProt Variants (confirmed using the germline classifier).", "Alternative variant ##chr12:25398285 C⇒G## (Gly12Arg) is classified Pathogenic by the VarSome community (confirmed using the germline classifier).", "Alternative variant ##chr12:25398285 C⇒A## (Gly12Cys) is classified Pathogenic by the VarSome community (confirmed using the germline classifier).", "Alternative variant ##chr12:25398284 C⇒G## (Gly12Ala) is classified Pathogenic by the VarSome community (confirmed using the germline classifier).", "Alternative variant ##chr12:25398284 C⇒A## (Gly12Val) is classified Pathogenic by UniProt Variants (confirmed using the germline classifier).", "Alternative variant ##chr12:25398284 CC⇒GA## (Gly12Ser) is classified Pathogenic by the VarSome community in article %%PUBMED:32308773%% (confirmed using the germline classifier).", "Alternative variant ##chr12:25398283 ACC⇒CCA## (Gly12Trp) is classified Pathogenic by the VarSome community in article %%PUBMED:33075161%% (confirmed using the germline classifier).", "7 pathogenic alternative variants identified." ], "strength": "Strong" }, { "name": "PP3", "met_criteria": true, "user_explain": [ "MetaRNN = 0.898 is between 0.841 and 0.939 ⇒ moderate pathogenic." ], "strength": "Moderate" }, { "name": "PP5", "met_criteria": true, "user_explain": [ "Combined evidence strength is Moderate (score = 2).", "Moderate: the VarSome community has classified this variant as Pathogenic, citing 16 articles (%%PUBMED:35075146%%, %%PUBMED:33917572%%, %%PUBMED:33538228%%, %%PUBMED:32810914%%, %%PUBMED:31409810%% and 11 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 609942, 615278, Acute Myeloid Leukemia, Arteriovenous Malformations of the Brain and 32 more, according to CGD, ClinGen Disease Validity, GenCC, Mondo, PanelApp and gene2phenotype.", "mode_of_inheritance": "AD, based on gene information from CGD, ClinGen Disease Validity, GenCC, Mondo, PanelApp and gene2phenotype." } }, "amp_annotation": { "version_name": "12.6.2", "verdict": { "tier": "Tier I", "approx_score": 3.345 }, "classifications": [ { "name": "Crtd", "tier": "Tier I", "user_explain": { "Tier I": [ "DoCM reports 4 entries classified Tier I citing 18 articles (%%PUBMED:23406027%%, %%PUBMED:22948721%%, %%PUBMED:21975775%%, %%PUBMED:21228335%%, %%PUBMED:20921465%% and 13 more) related to the following 4 cancers: Bowel, Non-Small Cell Lung Cancer, Ovary/Fallopian Tube and Thyroid." ], "Tier II": [ "ClinVar classifies this variant as Pathogenic, rated 2 stars related to the following 20 cancers: Acute Myeloid Leukemia, Acute granulocytic leukemia, Acute myelogenous leukemia, Acute non-lymphocytic leukemia, Colorectal Neoplasms and 15 more, with 28 somatic submissions, citing 51 articles (%%PUBMED:35794233%%, %%PUBMED:31891627%%, %%PUBMED:31836588%%, %%PUBMED:30936194%%, %%PUBMED:30443000%% and 46 more).", "DoCM reports 2 entries classified Tier II citing 8 articles (%%PUBMED:25157968%%, %%PUBMED:25044103%%, %%PUBMED:23014527%%, %%PUBMED:22407852%%, %%PUBMED:19075190%% and 3 more) related to the following 2 cancers: Acute Myeloid Leukemia and Lung.", "CIViC reports 11 entries, 9 x 3-star and 2 x 4-star rated , listing 4 drugs: \"Cetuximab\", \"Dactolisib\", \"Panitumumab\" and \"Selumetinib\" related to the following 4 cancers: Bowel, Lung, Ovary/Fallopian Tube and Pancreas.", "PMKB rates this variant Tier II citing 16 articles (%%PUBMED:27385790%%, %%PUBMED:27288520%%, %%PUBMED:26189129%%, %%PUBMED:26018876%%, %%PUBMED:24569456%% and 11 more) related to the following 27 cancers: Acute Leukemia Of Unspecified Cell Type, Acute Myeloid Leukemia, Adenocarcinoma, NOS, B-Lymphoblastic Leukemia/Lymphoma, Cholangiocarcinoma and 22 more." ] }, "approx_score": 3.2 }, { "name": "Drug", "tier": "Tier I", "user_explain": { "Tier I": [ "Cetuximab and Cetuximab, Panitumumab (curated), reported by CIViC, related to Bowel - but no patient cancer type was provided for matching.", "Docetaxel, Selumetinib (curated), reported by CIViC, related to Lung - but no patient cancer type was provided for matching." ], "Tier II": [ "15 drugs (curated), reported by CIViC, for 2 cancers (Bowel and Ovary/Fallopian Tube) - but no patient cancer type was provided for matching.", "11 drugs (curated), reported by CIViC and PMKB, for 2 cancers (Adenocarcinoma, NOS and Lung) - but no patient cancer type was provided for matching.", "Azd5438, Gemcitabine, Pi3Kbeta Inhibitor Azd8186 and Trametinib (curated), reported by CIViC, for 2 cancers (Cancer and Pancreatic Adenocarcinoma) - but no patient cancer type was provided for matching.", "Erlotinib and Erlotinib, Gemcitabine (curated), reported by CIViC, related to Pancreas - but no patient cancer type was provided for matching.", "Decitabine (curated), reported by CIViC, related to Ovary/Fallopian Tube - but no patient cancer type was provided for matching.", "Salirasib (curated), reported by CIViC, related to Lung Adenocarcinoma - but no patient cancer type was provided for matching." ] }, "approx_score": 5.0 }, { "name": "Germ", "tier": "Tier I", "user_explain": { "Tier I": [ "This variant is classified Pathogenic, by the germline classifier rules PS3_Very Strong, PM1_Strong, PM5_Strong, PP3_Moderate, PP5_Moderate and PM2_Supporting." ] }, "approx_score": 3.1 }, { "name": "Soma", "tier": "Tier I", "user_explain": { "Tier I": [ "This variant is reported in 5 967 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." ] }, "total_samples": 5967, "approx_score": 2.0 }, { "name": "Pubs", "tier": "Tier I", "user_explain": { "Tier I": [ "VarSome users have linked 21 articles stating the variant is pathogenic (%%PUBMED:39501138%%, %%PUBMED:36523988%%, %%PUBMED:36414681%%, %%PUBMED:35075146%%, %%PUBMED:33917572%% and 16 more)(4 entries have been automatically lifted over from hg38)." ] }, "approx_score": 3.0 }, { "name": "Path", "tier": "Tier II", "user_explain": { "Tier II": [ "Consensus associates gene KRAS with the following 29 cancers: Acute Myeloid Leukemia, Bladder/Urinary Tract, Breast, Central carbon metabolism in cancer, Choline metabolism in cancer and 24 more.", "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.", "KEGG reports that gene KRAS is involved in B cell receptor signaling pathway, ErbB signaling pathway, Fc epsilon RI signaling pathway, GnRH signaling pathway, Insulin signaling pathway and 3 more. Also, associates KRAS with the following 12 cancers: Acute Myeloid Leukemia, Bladder/Urinary Tract, Colorectal cancer, Endometrial cancer, Glioma and 7 more.", "Mondo associates gene KRAS with the following 12 cancers: Acute Myeloid Leukemia, Arteriovenous Malformations of the Brain, Autoimmune Lymphoproliferative Syndrome Type 4, Differentiated Thyroid Carcinoma, Familial Pancreatic Carcinoma and 7 more.", "The Human Protein Atlas classifies KRAS as an oncogene." ] }, "approx_score": 4.0 }, { "name": "Type", "tier": "Tier III", "user_explain": { "Tier III": [ "ACMG rule PVS1 did not trigger.", "ACMG rule PM4 did not trigger.", "Variant is not predicted splicing: no prediction from MaxEntScan." ] }, "approx_score": 2.0 }, { "name": "Freq", "tier": "Tier II", "user_explain": { "Tier II": [ "ACMG rule PM2 was triggered with strength Supporting: 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": 2.0 }, { "name": "Pred", "tier": "Tier III", "user_explain": { "Tier III": [ "Uncertain Significance computational verdict based on 1 pathogenic prediction from MetaRNN, conflicting with no benign predictions (and 1 uncertain prediction from DANN)." ] }, "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 }, { 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25157968, 26372703, 27872090, 29298116, 29525983, 29721857, 30463544 ], "oncotree_code": [ { "key": "PAAD", "value": 1358 }, { "key": "LUAD", "value": 643 }, { "key": "COAD", "value": 633 }, { "key": "COADREAD", "value": 344 }, { "key": "READ", "value": 244 }, { "key": "BOWEL", "value": 215 }, { "key": "PANCREAS", "value": 173 }, { "key": "UEC", "value": 151 }, { "key": "MAAP", "value": 134 }, { "key": "IHCH", "value": 113 }, { "key": "EHCH", "value": 71 }, { "key": "BLCA", "value": 66 }, { "key": "STAD", "value": 56 }, { "key": "NSCLC", "value": 55 }, { "key": "AML", "value": 54 }, { "key": "CHOL", "value": 49 }, { "key": "APAD", "value": 31 }, { "key": "AMPCA", "value": 31 }, { "key": "MACR", "value": 28 }, { "key": "LGSOC", "value": 26 }, { "key": "SBC", "value": 26 }, { "key": "CUP", "value": 17 }, { "key": "ESCA", "value": 16 }, { "key": "GEJ", "value": 15 }, { "key": "UTUC", "value": 14 }, { "key": "UCEC", "value": 13 }, { "key": "IDC", "value": 13 }, { "key": "BLL", "value": 12 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