Submissions for variant NM_000179.3(MSH6):c.806C>G (p.Thr269Ser)

dbSNP: rs587779322

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000684794	SCV000551228	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568144	SCV000673934	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The p.T269S variant (also known as c.806C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 806. The threonine at codon 269 is replaced by serine, an amino acid with similar properties. This alteration has been reported as an alteration of unknown clinical significance in a Danish Lynch syndrome cohort (Nilbert M et al, Fam. Cancer 2009 ; 8(1):75-83). It has also been reported as an uncertain variant in two individuals from a cohort of 815 patients with suspicion for HNPCC (Okkels H et al, Appl. Immunohistochem. Mol. Morphol. 2012 Oct; 20(5):470-7). This amino acid position is poorly 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759873	SCV000889507	uncertain significance	not provided	2017-09-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000568144	SCV001344140	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 269 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 an individual affected with endometrial cancer whose tumor displayed high microsatellite instability and mismatch repair deficiency (PMID: 33693762). This variant has been also been reported in several families suspected of Lynch syndrome (PMID: 18566915, 22495361). This variant has been identified in 3/251032 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	RCV000759873	SCV002499819	uncertain significance	not provided	2022-04-01	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 a history of Lynch syndrome associated cancers (Nilbert 2009, Okkels 2012); This variant is associated with the following publications: (PMID: 18566915, 22290698, 26333163, 22495361, 23621914, 32123317, 21437237)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267836	SCV002552284	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504983	SCV002814849	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-04-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997104	SCV004837041	uncertain significance	Lynch syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 269 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 an individual affected with endometrial cancer whose tumor displayed high microsatellite instability and mismatch repair deficiency (PMID: 33693762). This variant has been also been reported in several families suspected of Lynch syndrome (PMID: 18566915, 22495361). This variant has been identified in 3/251032 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.