Submissions for variant NM_000179.3(MSH6):c.727C>T (p.Arg243Cys)

gnomAD frequency: 0.00001  dbSNP: rs377216828

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132028	SCV000187087	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.R243C variant (also known as c.727C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 727. The arginine at codon 243 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients, who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with a high grade glioma (Zhang J et al. N. Engl. J. Med. 2015 Dec;373:2336-2346). 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.
Counsyl	RCV000410426	SCV000487921	uncertain significance	Lynch syndrome 5	2015-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464603	SCV000551083	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-11-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000480539	SCV000567222	uncertain significance	not provided	2022-02-23	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: 23621914, 21437237)
Color Diagnostics, LLC DBA Color Health	RCV000132028	SCV000908357	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 243 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 2/251088 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153428	SCV003843516	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410426	SCV004019002	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	RCV003462027	SCV004195535	uncertain significance	Endometrial carcinoma	2024-02-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998130	SCV004836886	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 243 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 2/251088 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689622	SCV005185268	uncertain significance	not specified	2024-05-09	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.727C>T (p.Arg243Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251088 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.727C>T has been reported in the literature in individuals affected with Breast cancer (Bhai_2021, Hu_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (ATM c.1924G>T, p.Glu642*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 35449176). ClinVar contains an entry for this variant (Variation ID: 142675). Based on the evidence outlined above, the variant was classified as uncertain significance.