Submissions for variant NM_000179.3(MSH6):c.980C>G (p.Thr327Ser)

gnomAD frequency: 0.00001  dbSNP: rs369568820

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164123	SCV000214738	likely benign	Hereditary cancer-predisposing syndrome	2024-02-12	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	RCV000204780	SCV000260205	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000479969	SCV000568902	uncertain significance	not provided	2023-05-05	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; Observed in individuals with ovarian, pancreatic, or prostate cancer (Pal et al., 2012; Grant et al., 2015; Lu et al., 2015); This variant is associated with the following publications: (PMID: 23621914, 25479140, 23047549, 21437237, 26689913)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479969	SCV000889512	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)), a Lynch syndrome-associated cancer (PMID: 31391288 (2020)), and breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH6). This variant has also been reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH6)). The frequency of this variant in the general population, 0.000039 (5/129124 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000164123	SCV000911932	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 327 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549) and pancreatic cancer (PMID: 25479140) in the literature. This variant has also been identified in 6/282796 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137692	SCV003807734	uncertain significance	Lynch syndrome 5	2022-06-01	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 supporting, PM2 moderated, BP4 supporting
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150013	SCV003837640	uncertain significance	Breast and/or ovarian cancer	2021-10-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528909	SCV004108498	uncertain significance	MSH6-related disorder	2023-07-02	criteria provided, single submitter	clinical testing	The MSH6 c.980C>G variant is predicted to result in the amino acid substitution p.Thr327Ser. This variant has been reported in individuals with ovarian or pancreatic cancer (Table S1, Pal et al. 2012. PubMed ID: 23047549; Table S1, Grant et al. 2015. PubMed ID: 25479140). An MSH6-specific in silico tool predicts that this variant does not impact protein function (Table 8, Terui et al. 2013. PubMed: 23621914). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026102-C-G) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184803/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000479969	SCV004146077	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	MSH6: PM2:Supporting, BP1, BP4
All of Us Research Program, National Institutes of Health	RCV003995316	SCV004837525	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 327 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549), pancreatic cancer (PMID: 25479140), and unspecified cancer (PMID: 31391288). In a large breast cancer case control study, this variant was reported in 7/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 6/282796 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.