Submissions for variant NM_004985.5(KRAS):c.34G>A (p.Gly12Ser)

gnomAD frequency: 0.00001  dbSNP: rs121913530

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038264	SCV000061933	pathogenic	Non-small cell lung carcinoma	2011-09-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000782191	SCV001248879	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851824	SCV002158725	pathogenic	RASopathy	2021-12-11	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 12584). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. This missense change has been observed in individuals with KRAS-related conditions (PMID: 17704260, 26242988). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the KRAS protein (p.Gly12Ser). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly12 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20805368, 22683711, 23096712, 23255105, 26521233). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
GeneDx	RCV000782191	SCV003805571	pathogenic	not provided	2023-02-26	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17704260, 26242988, 24803665, 25691160, 32948832, 34851763, 29493581, 17875937, 35753512, 21228335, 18794081, 17384584, 15696205, 35197282, 36756182, 32816843, 18594010, 23406027, 23096712, 22683711, 18316791, 16618717, 26521233, 25157968)
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004562205	SCV005049528	pathogenic	Vascular malformation	2024-04-10	criteria provided, single submitter	clinical testing	A KRAS c.34G>A (p.Gly12Ser) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in the literature in multiple individuals with vascular malformations (Hou YCC et al., PMID: 36571464). This variant has been reported in more than 2,000 cases in the cancer database COSMIC (COSMIC ID: COSV55497461). Other variants in the same codon (p.Gly12Ala, p.Gly12Arg, p.Gly12Asp, p.Gly12Cys, p.Gly12Val) have been reported in the individuals affected with arteriovenous/vascular malformations and are considered pathogenic/likely pathogenic (Hou YCC et al., PMID: 36571464; Hong T et al., PMID: 30544177; Nava C et al., PMID: 17704260; Joyce S et al., PMID: 26242988; Nikolaev SI et al., PMID: 29298116; Fish JE et al., PMID: 32552404; Priemer DS et al., PMID: 31026472, ClinVar Variation ID: 45122, 12582, 12578, 177778, 12583). 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 alterations in the "hotspot" codon 12 result in downstream MAPK/ERK pathway activation and tumor formation (Park JT, et al., PMID: 25065594). The KRAS gene is defined by the ClinGen RASopathy expert panel (Gelb BD et al., PMID: 29493581) as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and the ClinGen RASopathy expert panel guidelines (Gelb BD et al., PMID: 29493581), this variant is classified as pathogenic.
OMIM	RCV000013414	SCV000033661	pathogenic	Gastric cancer	2007-06-15	no assertion criteria provided	literature only
Laboratory of Translational Genomics, National Cancer Institute	RCV000119790	SCV000154262	not provided	Ovarian neoplasm		no assertion provided	not provided
OMIM	RCV000144971	SCV000191998	pathogenic	Juvenile myelomonocytic leukemia	2007-06-15	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000038264	SCV000504498	pathogenic	Non-small cell lung carcinoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432392	SCV000504499	pathogenic	Thyroid tumor	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445081	SCV000504500	pathogenic	Neoplasm of the large intestine	2014-10-02	no assertion criteria provided	literature only
Gharavi Laboratory, Columbia University	RCV000782191	SCV000920660	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000782191	SCV001554250	pathogenic	not provided		no assertion criteria provided	clinical testing