Submissions for variant NM_000251.3(MSH2):c.820A>G (p.Ile274Val)

gnomAD frequency: 0.00008  dbSNP: rs371944271

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167160	SCV000217991	likely benign	Hereditary cancer-predisposing syndrome	2022-05-30	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.
Invitae	RCV000198455	SCV000254430	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000587804	SCV000292620	likely benign	not provided	2018-09-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26976419, 23047549)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001248898	SCV000696288	uncertain significance	not specified	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.820A>G (p.Ile274Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 150746 control chromosomes (gnomAD v3.1, genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.820A>G has been reported in the literature in at-least one individual affected with epithelial ovarian cancer (Pal_2012). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MLH1 c.793C>T, p.Arg265Cys), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=5), Likely Benign (n=2) and Benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000663108	SCV000786225	uncertain significance	Lynch syndrome 1	2018-03-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587804	SCV001134376	uncertain significance	not provided	2018-11-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167160	SCV001343432	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 274 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 epithelial ovarian cancer (PMID: 23047549). This variant has been identified in 6/281746 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248898	SCV001422581	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Ile274Val variant in MSH2 has been reported in 1 individual with primary epithelial ovarian cancer (PMID: 23047549), and as been identified in 0.02407% (6/24926) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs371944271). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as a VUS by 5 submitters (Variation ID: 187433). The Isoleucine (Ile) at position 274 is not highly conserved in mammals and evolutionary distant species, and 12 species (Shrew, Tetraodon, Fugu, Nile tilapia, Burton's mouthbreeder, Princess of Burundi, Zebra mbuna, Pundamilia nyererei, Medaka, Stickleback, Atlantic cod, and Lamprey) carry a Valine (Val), raising the possibility that this change at this position may be tolerated. However, other computational prediction tools do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Ile274Met, has been reported as a VUS in association with disease in ClinVar (Variation ID: 472815). In summary, the clinical significance of the p.Ile274Val variant is uncertain. ACMG/AMP Criteria applied: None (Richards 2015).
Sema4, Sema4	RCV000167160	SCV002526752	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663108	SCV004018253	likely benign	Lynch syndrome 1	2023-03-17	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].
PreventionGenetics, part of Exact Sciences	RCV004535135	SCV004116251	uncertain significance	MSH2-related disorder	2023-03-09	criteria provided, single submitter	clinical testing	The MSH2 c.820A>G variant is predicted to result in the amino acid substitution p.Ile274Val. This variant has been identified in one individual with ovarian cancer (Supplementary Table 1 in Pal et al. 2012. PubMed ID: 23047549). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47641435-A-G) and is interpreted as a variant of uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187433/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000663108	SCV004196327	uncertain significance	Lynch syndrome 1	2023-08-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995565	SCV004831477	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 274 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 epithelial ovarian cancer (PMID: 23047549). This variant has been identified in 6/281746 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.