Submissions for variant NM_000179.3(MSH6):c.1037C>T (p.Ser346Phe)

dbSNP: rs567785169

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167468	SCV000218324	likely benign	Hereditary cancer-predisposing syndrome	2021-12-13	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	RCV000524097	SCV000283694	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 346 of the MSH6 protein (p.Ser346Phe). This variant is present in population databases (rs567785169, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 187718). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000229553	SCV000430956	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454816	SCV000539716	uncertain significance	not specified	2016-10-26	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: The p.Ser346Phe variant in MSH6 has not been previously reported in individuals with colorectal cancer. This variant has been identified in 1/66640 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs567785169). Serine (Ser) at position 346 is not conserved in mammals or evolutionarily distant species and 36 species (including 3 mammals) carry a Phenylalanine (Phe), raising the possibility that this change may be tolerated. Additional computational prediction tools suggest that the p.Ser346Phe variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ser346Phe variant is uncertain.
GeneDx	RCV000657019	SCV000566406	uncertain significance	not provided	2023-01-17	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21437237)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657019	SCV000601499	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251290 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy controls (PMID: 33471991 (2021)), see also LOVD ( http://databases.lovd.nl/shared/genes/MSH6)). 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.
Counsyl	RCV000662908	SCV000785833	uncertain significance	Lynch syndrome 5	2017-12-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167468	SCV000911012	likely benign	Hereditary cancer-predisposing syndrome	2016-03-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662908	SCV004018889	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000657019	SCV004224910	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	BP4, PM2