Submissions for variant NM_000179.3(MSH6):c.97C>A (p.Arg33Ser)

dbSNP: rs730881811

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000583826	SCV000690495	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 33 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685964	SCV000813466	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-07-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 33 of the MSH6 protein (p.Arg33Ser). 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: 491997). 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. 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.
Ambry Genetics	RCV000583826	SCV002689579	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	The p.R33S variant (also known as c.97C>A), located in coding exon 1 of the MSH6 gene, results from a C to A substitution at nucleotide position 97. The arginine at codon 33 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is poorly 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.
All of Us Research Program, National Institutes of Health	RCV004002359	SCV004827897	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 33 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.