Submissions for variant NM_000179.3(MSH6):c.1658C>G (p.Thr553Ser)

dbSNP: rs1553413038

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573994	SCV000673938	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.T553S variant (also known as c.1658C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1658. The threonine at codon 553 is replaced by serine, an amino acid with similar properties. This amino acid position is not well 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.
Invitae	RCV001202078	SCV001373177	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-08-23	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 485861). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 553 of the MSH6 protein (p.Thr553Ser).
Revvity Omics, Revvity	RCV003129928	SCV003808967	uncertain significance	not provided	2022-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330807	SCV004039443	uncertain significance	not specified	2023-08-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000573994	SCV004357607	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 553 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 not been identified 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.
All of Us Research Program, National Institutes of Health	RCV004001120	SCV004838871	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing