Submissions for variant NM_000251.3(MSH2):c.1963G>A (p.Val655Ile)

gnomAD frequency: 0.00003  dbSNP: rs549467183

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000662941	SCV000807673	uncertain significance	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	MLH1 methylation, but tumour with all proteins absent by IHC, proficient in CIMRA
GeneDx	RCV000115514	SCV000149423	likely benign	not provided	2021-04-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26845104, 28767289, 25186627, 30212499, 30262796, 33294277, 32659497, 31569399)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210146	SCV000266196	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000217714	SCV000273748	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	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	RCV001080304	SCV000284129	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000662941	SCV000785899	likely benign	Lynch syndrome 1	2018-01-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000115514	SCV000806017	likely benign	not provided	2017-05-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217714	SCV000903533	benign	Hereditary cancer-predisposing syndrome	2017-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780441	SCV000917691	benign	not specified	2022-05-12	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1963G>A (p.Val655Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251324 control chromosomes, predominantly at a frequency of 0.00075 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1963G>A has been reported in the literature in sequencing studies among individuals affected with breast, colorectal and pancreatic cancers (example, Shirts_2016, Tung_2015, Shindo_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported in the literature and at our laboratory (BRCA1 del exons 9-12, Tung_2015; ATM c.8264_8268delATAAG, p.Tyr2755fs*12, Internal testing data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories and one expert panel (InSIGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters have reported the variant with conflicting assessments (6 as benign/likely benign and 4 as a VUS). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115514	SCV002046760	uncertain significance	not provided	2022-07-06	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001836731	SCV002097657	uncertain significance	Mismatch repair cancer syndrome 1	2020-07-09	criteria provided, single submitter	clinical testing	The homozygous p.Val655Ile missense variant identified in MSH2 has been reported in the literature in individuals affected with pancreatic ductal adenocarcinoma [PMID: 28767289] and breast and ovarian cancer syndrome [PMID: 30262796]. The variant has been reported in ClinVar by multiple independent sources with conflicting interpretations about its pathogenicity [classified as benign, likely benign, and a variant of uncertain significance. Variation ID: 127637]. The p.Val655Ile variant is classified as a variant of uncertain significance by the ClinVar/ClinGen expert panel [Variation ID:127637]. The variant has 0.00003510 allele frequency in the gnomAD(v3) database (5 out of 142,452 heterozygous alleles), and 0.0001313 allele frequency in the “Exome subset” of gnomAD(v2) database (33 out of 251,324 heterozygous alleles, 1 homozygote). The affected residue is not well conserved. In Silico prediction tools provide conflicting interpretations about potential pathogenicity of this variant. Based on the current evidence, the p.Val655Ile variant in the MSH2 gene is assessed as a variant of uncertain significance.
Myriad Genetics, Inc.	RCV000662941	SCV004018332	likely benign	Lynch syndrome 1	2023-03-21	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].