Submissions for variant NM_000251.3(MSH2):c.835C>G (p.Leu279Val)

gnomAD frequency: 0.00003  dbSNP: rs375351205

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122993	SCV000166288	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131260	SCV000186225	likely benign	Hereditary cancer-predisposing syndrome	2020-06-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000656875	SCV000292621	likely benign	not provided	2021-04-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21056691, 18566915, 26976419, 27720647, 23729658)
Counsyl	RCV000409770	SCV000488719	uncertain significance	Lynch syndrome 1	2016-05-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000237042	SCV000601491	uncertain significance	not specified	2017-02-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131260	SCV000685134	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 279 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with rectal cancer and the tumor had detectable MSH2 by immunohistochemistry (PMID: 21056691), an individual affected with serrated polyposis syndrome and colorectal cancer (PMID: 35128723), and in a suspected Lynch syndrome family (PMID: 18566915). This variant also has been reported in an individual affected with breast cancer with a BRCA2 p.Tyr1894* covariant (PMID: 26976419), in two individuals affected with unspecified cancer (PMID: 31391288), and in a healthy control (PMID: 29641532). This variant has been identified in 15/280528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000237042	SCV000917682	uncertain significance	not specified	2022-10-26	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.835C>G (p.Leu279Val) results in a conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249628 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome (5.6e-05 vs 0.00057), allowing no conclusion about variant significance. c.835C>G has been reported in the literature in in individuals affected with colorectal cancer or other Lynch Syndrome-related cancers, including one individual who was also diagnosed with serrated polyposis syndrome and in an individual affected with breast cancer (e.g. Nilbert_2009, Limburg_2011, Tung_2014, Li_2020, Murphy_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. Co-occurrences with other pathogenic variants have been reported in the literature (BRCA2 c.5682C>A, p.Tyr1894X; Tung_2014) and UMD database (MLH1 c.117-1G>C), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS (n=7) and others classified the variant as likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000409770	SCV001737484	uncertain significance	Lynch syndrome 1	2021-06-04	criteria provided, single submitter	clinical testing	The MSH2 c.835C>G (p.Leu279Val) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47641450-C-G). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in at least one individual with colorectal cancer (PMID: 18566915, 21056691) and one individual with breast cancer (PMID: 26976419). It has also been reported in a non-cancer control subject (PMID: 29641532). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Genetic Services Laboratory, University of Chicago	RCV000237042	SCV002068639	uncertain significance	not specified	2019-03-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000237042	SCV002552205	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656875	SCV002822642	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409770	SCV004018300	likely benign	Lynch syndrome 1	2023-03-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV003997410	SCV004831500	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 279 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with rectal cancer and the tumor had detectable MSH2 by immunohistochemistry (PMID: 21056691), an individual affected with serrated polyposis syndrome and colorectal cancer (PMID: 35128723), and in a suspected Lynch syndrome family (PMID: 18566915). This variant also has been reported in an individual affected with breast cancer with a BRCA2 p.Tyr1894* covariant (PMID: 26976419), in two individuals affected with unspecified cancer (PMID: 31391288), and in a healthy control (PMID: 29641532). This variant has been identified in 15/280528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656875	SCV001550480	uncertain significance	not provided		no assertion criteria provided	clinical testing