Submissions for variant NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)

gnomAD frequency: 0.00001  dbSNP: rs121913529

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000272938	SCV000329383	pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000548006	SCV000659085	pathogenic	RASopathy	2017-06-30	criteria provided, single submitter	clinical testing	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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000029215	SCV001736991	pathogenic	Linear nevus sebaceous syndrome		criteria provided, single submitter	clinical testing
3billion	RCV000029215	SCV002318898	pathogenic	Linear nevus sebaceous syndrome	2022-03-22	criteria provided, single submitter	clinical testing	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.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000272938	SCV002525678	pathogenic	not provided	2021-08-13	criteria provided, single submitter	clinical testing	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000548006	SCV002601600	pathogenic	RASopathy	2022-10-05	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000272938	SCV002821689	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000585796	SCV004176950	pathogenic	Cerebral arteriovenous malformation	2023-11-03	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000013411	SCV000033658	pathogenic	Carcinoma of pancreas	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV002508117	SCV000033659	pathogenic	Gastric cancer	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV000022799	SCV000044088	pathogenic	Epidermal nevus	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV000029214	SCV000051860	pathogenic	Nevus sebaceous	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV000029215	SCV000051861	pathogenic	Linear nevus sebaceous syndrome	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV000144969	SCV000191996	pathogenic	Juvenile myelomonocytic leukemia	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV000144970	SCV000191997	pathogenic	Autoimmune lymphoproliferative syndrome type 4	2012-06-10	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000144969	SCV000198478	pathogenic	Juvenile myelomonocytic leukemia	2014-08-28	no assertion criteria provided	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150896	SCV000198479	pathogenic	Non-small cell lung carcinoma	2014-08-28	no assertion criteria provided	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150897	SCV000198480	pathogenic	Neoplasm of ovary	2014-08-28	no assertion criteria provided	clinical testing	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).
Database of Curated Mutations (DoCM)	RCV000426369	SCV000504481	pathogenic	Neoplasm of the large intestine	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433573	SCV000504482	likely pathogenic	Acute myeloid leukemia	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443973	SCV000504483	pathogenic	Thyroid tumor	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425250	SCV000504484	likely pathogenic	Lung carcinoma	2016-03-10	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000150897	SCV000504485	pathogenic	Neoplasm of ovary	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000150896	SCV000504486	pathogenic	Non-small cell lung carcinoma	2016-03-10	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000013411	SCV000504487	not provided	Carcinoma of pancreas	2016-03-10	no assertion provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV000029214	SCV000611562	pathogenic	Nevus sebaceous	2012-10-25	no assertion criteria provided	literature only
OMIM	RCV000585796	SCV000693723	pathogenic	Cerebral arteriovenous malformation	2018-03-06	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV000662266	SCV000784594	likely pathogenic	Vascular Tumors Including Pyogenic Granuloma	2015-02-19	no assertion criteria provided	literature only
Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center	RCV000150896	SCV000882686	pathogenic	Non-small cell lung carcinoma		no assertion criteria provided	research
Laboratory for Clinical Genomics and Advanced Technology, Dartmouth-Hitchcock Medical Center	RCV000013411	SCV000882700	pathogenic	Carcinoma of pancreas	2019-02-07	no assertion criteria provided	research	Variant causes impairment of the intrinsic GTPase activity of KRAS and subsequent activation of downstream signaling pathways that drive cancer growth.
Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School	RCV000585796	SCV000992585	pathogenic	Cerebral arteriovenous malformation		no assertion criteria provided	research
University Health Network, Princess Margaret Cancer Centre	RCV000856666	SCV000999192	pathogenic	Primary low grade serous adenocarcinoma of ovary	2019-11-04	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000272938	SCV001550138	pathogenic	not provided		no assertion criteria provided	clinical testing
Hematopathology, The University of Texas M.D. Anderson Cancer Center	RCV000433573	SCV001571657	pathogenic	Acute myeloid leukemia	2018-03-30	no assertion criteria provided	clinical testing
Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School	RCV001799604	SCV001739511	pathogenic	Capillary malformation-arteriovenous malformation 1	2021-05-01	no assertion criteria provided	research
GeneReviews	RCV001839445	SCV002099547	not provided	Encephalocraniocutaneous lipomatosis		no assertion provided	literature only
Martignetti Lab, Icahn School of Medicine at Mount Sinai	RCV003327361	SCV004035006	association	Endometrial hyperplasia without atypia; Atypical endometrial hyperplasia		no assertion criteria provided	research