Submissions for variant NM_000179.3(MSH6):c.2603T>C (p.Met868Thr)

gnomAD frequency: 0.00001  dbSNP: rs780280765

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000464988	SCV000551057	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-09-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771517	SCV000904021	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 868 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 hereditary cancer in the literature. This variant has been identified in 1/249912 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798840	SCV002042042	uncertain significance	Breast and/or ovarian cancer	2021-05-05	criteria provided, single submitter	clinical testing
GeneDx	RCV002289613	SCV002578379	uncertain significance	not provided	2022-04-06	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: 17531815, 21120944)
Ambry Genetics	RCV000771517	SCV002740684	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The p.M868T variant (also known as c.2603T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 2603. The methionine at codon 868 is replaced by threonine, an amino acid with similar properties. 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.
All of Us Research Program, National Institutes of Health	RCV004000830	SCV004842771	uncertain significance	Lynch syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 868 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 hereditary cancer in the literature. This variant has been identified in 1/249912 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.