Submissions for variant NM_000179.3(MSH6):c.1561A>T (p.Thr521Ser)

dbSNP: rs587779916

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115377	SCV000149286	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1561A>T at the cDNA level, p.Thr521Ser (T521S) at the protein level, and results in the change of a Threonine to a Serine (ACA>TCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Thr521Ser was not observed in large population cohorts (Lek 2016). This variant is located in Connector domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Thr521Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000216113	SCV000273052	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The p.T521S variant (also known as c.1561A>T), located in coding exon 4 of the MSH6 gene, results from an A to T substitution at nucleotide position 1561. The threonine at codon 521 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000473285	SCV000551253	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 521 of the MSH6 protein (p.Thr521Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 127560). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493444	SCV004243089	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216113	SCV004357596	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 521 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 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	RCV003997234	SCV004839484	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 521 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 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.