Submissions for variant NM_000179.3(MSH6):c.2291C>A (p.Thr764Asn)

gnomAD frequency: 0.00001  dbSNP: rs561198849

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163700	SCV000214274	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	The p.T764N variant (also known as c.2291C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 2291. The threonine at codon 764 is replaced by asparagine, an amino acid with similar properties. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability; however, this variant was seen in conjunction with a pathogenic MLH1 variant (Casey G et al. JAMA 2005 Feb;293(7):799-809). This variant was also reported in one of 711 Russian women with breast cancer but was absent from 492 healthy controls. The patient with this variant also reportedly carried a BRCA2 pathogenic mutation (Nikitin AG et al. Front Oncol, 2020 May;10:666). This amino acid position is not well 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.
GeneDx	RCV000480884	SCV000568722	uncertain significance	not provided	2020-12-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast cancer (Nikitin 2020); Observed in an individual in published literature (Casey 2005) who had a different genetic etiology for colorectal cancer; This variant is associated with the following publications: (PMID: 15713769, 23621914, 32547938)
Color Diagnostics, LLC DBA Color Health	RCV000163700	SCV000685277	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 764 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 an individual with colorectal cancer, however, this individual also carried a pathogenic variant in the MLH1 gene that could explain the observed phenotype (PMID: 15713769). This variant has also been reported in an individual affected with hereditary breast cancer (PMID: 32547938). This variant has been identified in 5/282546 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.
Invitae	RCV000630065	SCV000751021	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000662379	SCV000784776	uncertain significance	Lynch syndrome 5	2017-12-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480884	SCV001134410	uncertain significance	not provided	2019-08-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163700	SCV002535717	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307420	SCV002600391	uncertain significance	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2291C>A (p.Thr764Asn) results in a non-conservative amino acid change DNA mismatch repair protein MutS core (IPR007696) 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 1.6e-05 in 251148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2291C>A has been reported in the literature in individuals affected with Colorectal cancer and Breast cancer without stong evidence for causality (Casey_2005, Nikitin_2020). These data do not allow any conclusion about variant significance. Co-occurrence with another pathogenic variant have been reported (MLH1 c.350C>G, p.Thr117Arg), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000662379	SCV004018901	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.
Baylor Genetics	RCV003462122	SCV004197639	uncertain significance	Endometrial carcinoma	2023-10-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995273	SCV004841983	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 764 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 an individual with colorectal cancer, however, this individual also carried a pathogenic variant in the MLH1 gene that could explain the observed phenotype (PMID: 15713769). This variant has also been reported in an individual affected with hereditary breast cancer (PMID: 32547938). This variant has been identified in 5/282546 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.