Submissions for variant NM_000251.3(MSH2):c.2009C>T (p.Pro670Leu)

gnomAD frequency: 0.00002  dbSNP: rs41294982

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524371	SCV000259265	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220086	SCV000275632	likely benign	Hereditary cancer-predisposing syndrome	2022-02-23	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.
GeneDx	RCV000483333	SCV000565199	uncertain significance	not provided	2020-10-19	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer whose tumor demonstrated intact mismatch repair protein expression and microsatellite stability (Barnetson 2008); This variant is associated with the following publications: (PMID: 17250671, 19047842, 22290698, 19389263, 26333163, 18033691, 31391288)
Color Diagnostics, LLC DBA Color Health	RCV000220086	SCV000690040	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 670 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 at least one individual affected with colorectal cancer whose tumor sample showed microsatellite stability and the presence of MLH1, MSH2, and MSH6 proteins by immunohistochemistry (PMID: 18033691). This variant has been identified in 4/282764 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.
Fulgent Genetics, Fulgent Genetics	RCV000765672	SCV000897014	uncertain significance	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265597	SCV002547925	likely benign	not specified	2022-05-31	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2009C>T (p.Pro670Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251370 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2009C>T has been reported in the literature in an individual with MSS-stable colorectal cancer that tested positive for MLH1, MSH2 and MSH6 by tumor immunohistochemistry (IHC) (Barneston_2008) and also in a study reporting computed tumour characteristic likelihood ratio (TCLR) based on MSI/IHC status, and estimated likelihood ratios (Li_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been reported in the UMD database (MSH6 c.755C>A , p.Ser252X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Jia_2021). These results showed no damaging effect of this variant on mismatch repair (MMR) in a high throughput massively parallel functional testing assay. 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 likely benign.
All of Us Research Program, National Institutes of Health	RCV003997156	SCV004825150	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 670 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 at least one individual affected with colorectal cancer whose tumor sample showed microsatellite stability and the presence of MLH1, MSH2, and MSH6 proteins by immunohistochemistry (PMID: 18033691). This variant has been identified in 4/282764 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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003389040	SCV004101135	uncertain significance	Lynch syndrome 1	2023-11-02	no assertion criteria provided	clinical testing