Submissions for variant NM_004985.5(KRAS):c.35G>T (p.Gly12Val)

dbSNP: rs121913529

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150895	SCV000198477	pathogenic	Juvenile myelomonocytic leukemia	2018-02-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154262	SCV000203917	pathogenic	Non-small cell lung carcinoma	2018-02-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000157944	SCV000207879	pathogenic	not provided	2020-01-25	criteria provided, single submitter	clinical testing	Observed as a somatic variant in intracranial AVM specimens and sebaceous nevi (Goss et al., 2019; Groesser et al., 2012; Levinsohn et al., 2013); Observed as a presumably somatic variant associated with malignancies including non-small cell lung cancer, pancreatic carcinoma, and ovarian carcinoma (Doebele et al., 2012; Motojima et al., 1993); Auner et al., 2009); Published functional studies demonstrated that G12V impaired function and enhanced downstream signaling (Gremer et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 15696205, 22669205, 21169357, 17384584, 2278970, 21975775, 25157968, 24803665, 23096712, 19047918, 19018267, 18316791, 17704260, 16618717, 19679400, 19075190, 29298116, 22897852, 22407852, 21398618, 21228335, 20609353, 19881948, 20949621, 31891627, 26372703, 22683711, 22235099, 8439212, 19358724)
CeGaT Center for Human Genetics Tuebingen	RCV000157944	SCV001746133	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003455987	SCV004176921	pathogenic	Linear nevus sebaceous syndrome	2023-09-22	criteria provided, single submitter	clinical testing	The KRAS c.35G>T (p.Gly12Val) variant was identified at an allelic fraction consistent with somatic origin. It has been identified in individuals with Schimmelpenning-Feuerstein-Mims syndrome and arteriovenous malformation caused by somatic pathogenic variants (Groesser L et al., PMID: 22683711; Serio VB et al., PMID: 35807022; Palmieri M et al., PMID: 34617046; Ten Broek RW et al., PMID: 30677207; Al-Olabi L et al., PMID: 29461977). This variant has been reported in the ClinVar database as pathogenic by eight submitters (ClinVar ID: 12583) in both a germline and a somatic state. It also has been reported in 11,239 cases in the cancer database (COSMIC ID: COSV55497419). KRAS c.35G>T (p.Gly12Val) is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the switch I region, amino acids 32-40, of KRAS that is defined as a critical functional domain (Pacold ME et al., PMID: 11136978). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KRAS function. The KRAS gene is defined by ClinGen’s RASopathy 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: 2949358). Functional studies using animals show that this variant induces vascular malformation phenotypes similar to observed in humans (Fish JE et al., PMID: 32552404). Other variants in the same codon, c.35G>A (p.Gly12Asp) have been reported in individuals with Schimmelpenning-Feuerstein-Mims syndrome and nevus sebaceous and are considered pathogenic (Mitchell BJ et al., PMID: 30394973; Levinsohn JL et al., PMID: 23096712; ClinVar ID: 12582). 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, KRAS c.35G>T (p.Gly12Val) variant is classified as pathogenic.
Invitae	RCV003539760	SCV004295856	pathogenic	RASopathy	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the KRAS protein (p.Gly12Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 12583). 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. Experimental studies have shown that this missense change affects KRAS function (PMID: 20949621, 21044336). 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: 17704260, 26242988). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000013413	SCV000033660	pathogenic	Carcinoma of pancreas	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV000029216	SCV000051862	pathogenic	Nevus sebaceous	2012-06-10	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439750	SCV000504471	likely pathogenic	Acute myeloid leukemia	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417765	SCV000504472	pathogenic	Thyroid tumor	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428010	SCV000504473	pathogenic	Neoplasm of ovary	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439101	SCV000504474	pathogenic	Neoplasm of the large intestine	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000154262	SCV000504475	likely pathogenic	Non-small cell lung carcinoma	2016-03-10	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV000029216	SCV000611561	pathogenic	Nevus sebaceous	2012-10-25	no assertion criteria provided	literature only
OMIM	RCV000585801	SCV000693724	pathogenic	Cerebral arteriovenous malformation	2018-03-06	no assertion criteria provided	literature only
Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School	RCV000585801	SCV000992586	pathogenic	Cerebral arteriovenous malformation		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000157944	SCV001553731	pathogenic	not provided		no assertion criteria provided	clinical testing
Druker Lab, Oregon Health and Sciences University	RCV002291496	SCV002583834	pathogenic	Chronic myelogenous leukemia, BCR-ABL1 positive	2022-10-10	no assertion criteria provided	clinical testing
Salgia Laboratory, City of Hope	RCV003322589	SCV003804201	pathogenic	Lung sarcomatoid carcinoma		no assertion criteria provided	clinical testing