Submissions for variant NM_000251.3(MSH2):c.508C>G (p.Gln170Glu)

gnomAD frequency: 0.00011  dbSNP: rs63750843

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204442	SCV000260484	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214137	SCV000274325	likely benign	Hereditary cancer-predisposing syndrome	2023-02-28	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.
Color Diagnostics, LLC DBA Color Health	RCV000214137	SCV000685096	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 170 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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: 35039564). This variant has been identified in 8/282864 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759837	SCV000889442	likely benign	not provided	2023-08-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000759837	SCV001825824	uncertain significance	not provided	2020-12-04	criteria provided, single submitter	clinical testing	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
Fulgent Genetics, Fulgent Genetics	RCV002485345	SCV002784322	uncertain significance	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-05-16	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315420	SCV004015212	uncertain significance	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 170 of the MSH2 protein (p.Gln170Glu). This variant is present in population databases (rs63750843, gnomAD 0.03%). This missense change has been observed in individual(s) with MSH2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 220157) with 5 submissions. In-silico predictions (SIFT and PholyPhen) show this variant to be tolerated. Therefore, it has been classified as a Variant of Uncertain Significance. Heterozygous pathogenic mutations in the MSH2 cause hereditary nonpolyposis colorectal cancer syndrome.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320603	SCV004025229	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003315420	SCV004196260	uncertain significance	Lynch syndrome 1	2023-09-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997618	SCV004832489	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 170 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/282864 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.