Submissions for variant NM_000179.3(MSH6):c.1607G>C (p.Ser536Thr)

gnomAD frequency: 0.00001  dbSNP: rs587782352

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491862	SCV000580195	likely benign	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000822280	SCV000963075	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-08-09	criteria provided, single submitter	clinical testing	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 serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 536 of the MSH6 protein (p.Ser536Thr). ClinVar contains an entry for this variant (Variation ID: 428340). 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. 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.
Baylor Genetics	RCV003464048	SCV004197603	uncertain significance	Endometrial carcinoma	2023-10-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491862	SCV004357602	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 536 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 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	RCV004003456	SCV004839595	uncertain significance	Lynch syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 536 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 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.