Submissions for variant NM_000251.3(MSH2):c.2537A>G (p.Gln846Arg)

gnomAD frequency: 0.00015  dbSNP: rs140754514

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656883	SCV000211219	likely benign	not provided	2019-02-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000160621	SCV000215957	likely benign	Hereditary cancer-predisposing syndrome	2020-05-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000168241	SCV000218911	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160621	SCV000685052	likely benign	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235176	SCV000712847	uncertain significance	not specified	2017-02-20	criteria provided, single submitter	clinical testing	The p.Gln846Arg variant in MSH2 has not been previously reported in individuals with colorectal cancer. This variant has been identified in 3/10406 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs140754514). Computational prediction tools and conservation analysis suggest that the p.Gln846Arg variant may not impact the protein, though this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the p.Gln846Arg variant is uncertain.
Counsyl	RCV000663089	SCV000786184	uncertain significance	Lynch syndrome 1	2018-03-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000656883	SCV000806031	uncertain significance	not provided	2017-10-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656883	SCV000889429	uncertain significance	not provided	2021-05-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235176	SCV001774573	uncertain significance	not specified	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2537A>G (p.Gln846Arg) 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 5.6e-05 in 251440 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (5.6e-05 vs 0.00057), allowing no conclusion about variant significance. c.2537A>G has been reported in the literature in individuals affected with cancer, without strong evidence for causality (Gordon_2019, Li_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31422818, 31391288). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: five classified as VUS while three classified as likely benign/benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000663089	SCV004018314	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].
Baylor Genetics	RCV000663089	SCV004196256	uncertain significance	Lynch syndrome 1	2023-09-13	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235176	SCV000691912	uncertain significance	not specified		no assertion criteria provided	clinical testing