Submissions for variant NM_000251.3(MSH2):c.362A>G (p.Tyr121Cys)

gnomAD frequency: 0.00001  dbSNP: rs587779971

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115527	SCV000149436	uncertain significance	not provided	2023-10-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with juvenile polyposis syndrome who also harbored a canonical splice variant in SMAD4 (Micolonghi et al., 2022); Published functional study demonstrates mismatch repair activity similar to wild-type (Jia et al., 2020); This variant is associated with the following publications: (PMID: 18822302, 21120944, 25318351, 27720647, 36359527, 33357406)
Ambry Genetics	RCV000220764	SCV000277258	benign	Hereditary cancer-predisposing syndrome	2022-09-30	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000226077	SCV000284168	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220764	SCV000685082	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 121 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 9/282148 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000115527	SCV000885711	uncertain significance	not provided	2017-07-27	criteria provided, single submitter	clinical testing	The MSH2 c.362A>G;p.Tyr121Cys variant has been published in the medical literature in at least one individual suspected of having hereditary cancer (Mu 2016). The variant is listed in the ClinVar database (Variation ID: 127643) and the dbSNP variant database (rs587779971) with an allele frequency of 0.003253 percent (9/276636 alleles) in the Genome Aggregation Database. The amino acid at this position is located in the mismatch binding domain (Lutzen 2008), but the amino acid is weakly conserved and computational algorithms do not reach a consensus as to the effect of this variant (AlignGVGD: C15, SIFT: Tolerated, MutationTaster: disease causing). However, this variant occurs near an exon/intron boundary and splicing prediction programs (SpliceSiteFinder-like, MaxEntScan, NNSplice, GeneSplicer, Human Splicing Finder) predict this variant may alter splicing. Considering available information, there is insufficient evidence to classify the variant at this time. Pathogenic MSH2 variants are causative for Lynch syndrome (MIM#120435). References Lutzen A et al. Functional analysis of HNPCC-related missense mutations in MSH2. Mutat Res. 2008 Oct 14;645(1-2):44-55. Mu W et al. Sanger Confirmation Is Required to Achieve Optimal Sensitivity and Specificity in Next-Generation Sequencing Panel Testing. J Mol Diagn. 2016 Nov;18(6):923-932.
Division of Medical Genetics, University of Washington	RCV001257467	SCV001434270	uncertain significance	Lynch syndrome 1	2020-01-22	criteria provided, single submitter	clinical testing	This variant has been reported in the literature as identified on hereditary cancer gene panel testing (Mu 2016). This variant has an overall allele frequency of 0.00003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387764	SCV004100269	uncertain significance	not specified	2023-09-29	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.362A>G (p.Tyr121Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250740 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.362A>G has been reported in the literature in individuals affected with breast and ovarian cancer without strong evidence for causality (examples: Harismendy_2013 and Li_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. 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: 24326041, 30584090). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000115527	SCV004224902	uncertain significance	not provided	2022-12-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997278	SCV004830054	uncertain significance	Lynch syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 121 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 9/282148 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.