Submissions for variant NM_000251.3(MSH2):c.266T>C (p.Val89Ala)

gnomAD frequency: 0.00001  dbSNP: rs876659747

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215101	SCV000276538	benign	Hereditary cancer-predisposing syndrome	2023-08-11	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	RCV000227027	SCV000284157	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215101	SCV000906757	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 89 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). This variant has been reported in individuals affected with breast cancer (PMID: 28580595, 35449176), and in several individuals affected with unspecified cancer (PMID: 31386297, 31391288). This variant has also been identified in 3/282588 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030705	SCV001193627	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532987	SCV001748820	uncertain significance	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.266T>C (p.Val89Ala) 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. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251212 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.266T>C has been reported in the literature as a VUS in settings of multigene cancer panel testing on patients with breast and colorectal cancer (example, Xie_2018, Kiyozumi_2019, Li_2020_Hu_2022). One of these reports estimated the tumor characteristic likelihood ratio (TCLR) for this variant as likely benign (Li_2020). These reports 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: 28580595, 31386297, 31391288, 35449176). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997972	SCV004824262	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 89 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). This variant has been reported in individuals affected with breast cancer (PMID: 28580595, 35449176), and in several individuals affected with unspecified cancer (PMID: 31386297, 31391288). This variant has also been identified in 3/282588 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.