Submissions for variant NM_000251.3(MSH2):c.1360A>G (p.Ile454Val)

gnomAD frequency: 0.00001  dbSNP: rs587781627

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129729	SCV000184534	likely benign	Hereditary cancer-predisposing syndrome	2018-11-07	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	RCV000460057	SCV000548202	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000588274	SCV000565191	uncertain significance	not provided	2023-04-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30122538, 18822302, 21120944, 30787465)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588274	SCV000696208	uncertain significance	not provided	2017-03-20	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1360A>G (p.Ile454Val) variant causes a missense change involving the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant is absent in 119816 control chromosomes. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761179	SCV000891095	uncertain significance	Lynch syndrome	2020-10-01	criteria provided, single submitter	clinical testing	The MSH2 c.1360A>G (p.Ile454Val) missense change has a maximum subpopulation frequency of 0.0023% gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-47672770-A-G). In silico tools are not in agreement about a tolerated or damaging effect on the gene or protein product and functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting.
Color Diagnostics, LLC DBA Color Health	RCV000129729	SCV000908302	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 454 of the MSH2 protein. Computational prediction tool 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 3/282080 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.1361T>A (p.Ile454Lys) and c.1361T>G (p.Ile454Arg), are described to be disease-causing (ClinVar variation ID: 1770848, 495768), suggesting that this position may be important for the protein function. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267870	SCV002552227	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000761179	SCV004831040	uncertain significance	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 454 of the MSH2 protein. Computational prediction tool 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 3/282080 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.1361T>A (p.Ile454Lys) and c.1361T>G (p.Ile454Arg), are described to be disease-causing (ClinVar variation ID: 1770848, 495768), suggesting that this position may be important for the protein function. 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.