Submissions for variant NM_000179.3(MSH6):c.494T>G (p.Phe165Cys)

gnomAD frequency: 0.00001  dbSNP: rs763841886

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215845	SCV000274884	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-18	criteria provided, single submitter	clinical testing	The p.F165C variant (also known as c.494T>G), located in coding exon 3 of the MSH6 gene, results from a T to G substitution at nucleotide position 494. The phenylalanine at codon 165 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000534390	SCV000624978	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215845	SCV000685494	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 165 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 MSH6-related disorders in the literature. This variant has been identified in 2/251434 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	RCV001762481	SCV002007842	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Obsvered in an individual with clear cell renal carcinoma, as well as in individuals with unspecified tumors evaluated by microsatellite instability and mismatch repair immunohistochemistry (Li et al., 2020; Schwartz et al., 2022); This variant is associated with the following publications: (PMID: 18566663, 22949387, 31391288, 36091175, 33471991)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001762481	SCV004222043	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000018 (2/113714 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with cancer assessed by microsatellite instability (PMID: 31391288 (2020)). In a large-scale breast cancer association study, the variant was observed in a control individual and not among the breast cancer cases (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 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	RCV003997884	SCV004829297	uncertain significance	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 165 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251434 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.