Submissions for variant NM_000251.3(MSH2):c.1087G>T (p.Val363Leu)

gnomAD frequency: 0.00007  dbSNP: rs377345366

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479898	SCV000566532	uncertain significance	not provided	2024-02-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast cancer or leukemia (PMID: 29684080, 26580448, 33471991); This variant is associated with the following publications: (PMID: 29684080, 26580448, 33471991, 18822302, 21120944)
Ambry Genetics	RCV000561329	SCV000662213	likely benign	Hereditary cancer-predisposing syndrome	2019-01-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629790	SCV000750746	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000561329	SCV000908294	likely benign	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821392	SCV002070736	uncertain significance	not specified	2020-12-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1087G>T, in exon 7 that results in an amino acid change, p.Val363Leu. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders and has been described in the gnomAD database with a frequency of 0.029% in the African sub-population (dbSNP rs377345366). The p.Val363Leu change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Val363Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val363Leu change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821392	SCV002511450	uncertain significance	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1087G>T (p.Val363Leu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) 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 2e-05 in 250292 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1087G>T has been reported in the literature in individuals affected with Leukemia and Prostate Cancer (Zhang_2015, Trendowski_2022) without evidence for causality. These reports 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: 36446039, 26580448). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=2) and VUS (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000561329	SCV002528811	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-04	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004002282	SCV004827098	likely benign	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 363 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with leukemia (PMID: 26580448), or breast/ovarian cancer (PMID: 29684080, 34359559). This variant has been identified in 9/281694 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.