Submissions for variant NM_000179.3(MSH6):c.94G>T (p.Gly32Cys)

gnomAD frequency: 0.00002  dbSNP: rs776859837

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198127	SCV000254338	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000480324	SCV000568988	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Not observed at a 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 a personal or family history of breast, pancreatic, or ovarian cancer (Caminsky 2016, Shindo 2017, Hu 2020); This variant is associated with the following publications: (PMID: 22949387, 26898890, 28767289, 32659497)
Ambry Genetics	RCV000564851	SCV000662540	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-03	criteria provided, single submitter	clinical testing	The p.G32C variant (also known as c.94G>T), located in coding exon 1 of the MSH6 gene, results from a G to T substitution at nucleotide position 94. The glycine at codon 32 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was observed in multiple cohorts of individuals diagnosed with pancreatic adenocarcinoma (Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg, 2020 11;231:527-535.e14). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000663156	SCV000786311	uncertain significance	Lynch syndrome 5	2018-04-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480324	SCV000889511	uncertain significance	not provided	2024-11-22	criteria provided, single submitter	clinical testing	The MSH6 c.94G>T (p.Gly32Cys) variant has been reported in the published literature in individuals with pancreatic cancer (PMIDs: 28767289 (2017) and 32659497 (2020)), breast cancer (PMIDs: 26898890 (2016) and 34326862 (2021)), as well as in an individual with colorectal cancer (PMID: 37937776 (2023)). The frequency of this variant in the general population, 0.000034 (4/119152 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	RCV000564851	SCV001339378	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 32 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 reported for this variant. This variant has been reported in individuals affected with pancreatic (PMID: 28767289), or breast cancer (PMID: 26898890). This variant has been identified in 7/266950 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.
Myriad Genetics, Inc.	RCV000663156	SCV004018884	uncertain significance	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317146	SCV004020494	uncertain significance	not specified	2023-06-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.94G>T (p.Gly32Cys) results in a non-conservative amino acid change located in the PWWP domain (IPR000313) 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 2.1e-05 in 235638 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.94G>T has been reported in the literature in individuals affected with breast cancer or pancreatic cancer (examples: Caminsky_2016, Shindo_2017). These report(s) 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: 26898890, 28767289). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as uncertain significance (n=5) or likely beningn (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003317146	SCV004024778	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530189	SCV004114885	uncertain significance	MSH6-related disorder	2023-08-17	criteria provided, single submitter	clinical testing	The MSH6 c.94G>T variant is predicted to result in the amino acid substitution p.Gly32Cys. This variant was reported as a variant of uncertain significance in individuals with pancreatic ductal adenocarcinoma (Shindo et al 2017. PubMed ID: 28767289; eAppendix 1, Hu et al. 2020. PubMed ID: 32659497). This variant was also reported in an individual from a hereditary breast and ovarian cancer cohort (Patient 14-6C in Table S13A, Caminsky et al. 2016. PubMed ID: 26898890). This variant is reported in 0.0091% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48010466-G-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/216325/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003997005	SCV004827886	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 32 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 reported for this variant. This variant has not been reported in individuals affected with pancreatic (PMID: 28767289), or breast cancer (PMID: 26898890). This variant has been identified in 7/266950 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.