Submissions for variant NM_000179.3(MSH6):c.2177T>A (p.Phe726Tyr)

gnomAD frequency: 0.00001  dbSNP: rs574358605

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524133	SCV000551268	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568729	SCV000662472	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	clinical testing	The p.F726Y variant (also known as c.2177T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 2177. The phenylalanine at codon 726 is replaced by tyrosine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000662512	SCV000785051	uncertain significance	Lynch syndrome 5	2017-03-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000568729	SCV000908391	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with tyrosine at codon 726 of the MSH6 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. In a large breast cancer case-control study, this variant has been reported in 4/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/250960 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.
GeneDx	RCV001582560	SCV001812491	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this 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: 26333163, 17531815, 21120944)
Myriad Genetics, Inc.	RCV000662512	SCV004019052	uncertain significance	Lynch syndrome 5	2023-03-29	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.
Baylor Genetics	RCV003466941	SCV004195644	uncertain significance	Endometrial carcinoma	2023-07-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001582560	SCV004221171	uncertain significance	not provided	2023-01-16	criteria provided, single submitter	clinical testing	The variant has not been reported in individuals with MSH6-related cancers in the published literature. In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as unaffected control individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.000026 (3/113280 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997072	SCV004836118	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with tyrosine at codon 726 of the MSH6 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer and in healthy control individuals (PMID: 33471991). This variant has been identified in 3/250960 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.
Clinical Genetics, Academic Medical Center	RCV001582560	SCV001918277	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001582560	SCV001952763	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001582560	SCV001967579	uncertain significance	not provided		no assertion criteria provided	clinical testing