Submissions for variant NM_000251.3(MSH2):c.160G>T (p.Ala54Ser)

dbSNP: rs749212640

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164978	SCV000215671	likely benign	Hereditary cancer-predisposing syndrome	2023-06-15	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	RCV000200570	SCV000254388	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000663139	SCV000786286	uncertain significance	Lynch syndrome 1	2018-04-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781570	SCV000919722	uncertain significance	not specified	2021-11-14	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.160G>T (p.Ala54Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal 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 4.3e-06 in 232470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.160G>T in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000781570	SCV001160017	uncertain significance	not specified	2018-10-16	criteria provided, single submitter	clinical testing	The MSH2 c.160G>T; p.Ala54Ser variant (rs749212640) is reported as a variant of uncertain significance in the medical literature (DeRycke 2017). The variant is described as a variant of uncertain significance in the ClinVar database (Variation ID: 185536) the variant is found in the general population with an allele frequency of 0.0004% (1/228144 alleles) in the Genome Aggregation Database. The alanine at this position is highly conserved but computational analyses (SIFT: Tolerated, PolyPhen-2:Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Based on available information, this variant is classified as a variant of uncertain significance.
GeneDx	RCV001589031	SCV001823193	uncertain significance	not provided	2019-10-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27150160)
Genetic Services Laboratory, University of Chicago	RCV000781570	SCV002072331	uncertain significance	not specified	2019-04-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663139	SCV004018262	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].
All of Us Research Program, National Institutes of Health	RCV003995379	SCV004831905	uncertain significance	Lynch syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 54 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 a cohort of individuals affected with Lynch syndrome-associated cancer (PMID: 36793599). This variant has been identified in 1/232470 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.