Submissions for variant NM_000251.3(MSH2):c.819A>G (p.Val273=)

gnomAD frequency: 0.00101  dbSNP: rs146577635

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082291	SCV000166287	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000212592	SCV000211243	benign	not specified	2014-09-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000160641	SCV000212735	likely benign	Hereditary cancer-predisposing syndrome	2014-06-30	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.
Color Diagnostics, LLC DBA Color Health	RCV000160641	SCV000685132	likely benign	Hereditary cancer-predisposing syndrome	2015-10-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586418	SCV000696287	benign	not provided	2016-02-23	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.819A>G variant affects a non-conserved nucleotide, resulting in no amino acid change. Mutation Taster predicts a damaging outcome for this variant, and 2/5 Alamut algorithms predict no significant change to normal splicing and no changes to ESE binding sites. The variant of interest has not been evaluated for functional impact by in vivo/vitro studies. This variant is found in 31/121148 control chromosomes at a frequency of 0.0002559, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0005683). However, the allele frequency in Africans (29/10308; 0.002813) is 5-fold greater than the maximal expected allele frequency for a pathogenic MSH2 variant, suggesting that this is a benign polymorphism found in Africans. In addition, clinical laboratories classified this variant as likely benign/benign. Taken together, this variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000586418	SCV000806050	likely benign	not provided	2017-07-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212592	SCV000888235	benign	not specified	2022-07-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001139365	SCV001299508	uncertain significance	Lynch syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago	RCV000212592	SCV002071657	likely benign	not specified	2017-10-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160641	SCV002526751	benign	Hereditary cancer-predisposing syndrome	2021-02-03	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001139365	SCV004015948	benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586418	SCV004563888	likely benign	not provided	2023-04-13	criteria provided, single submitter	clinical testing