Submissions for variant NM_000179.3(MSH6):c.98G>C (p.Arg33Pro)

gnomAD frequency: 0.00001  dbSNP: rs878853751

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000230339	SCV000283866	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-09	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. 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. This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 33 of the MSH6 protein (p.Arg33Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 23523604). ClinVar contains an entry for this variant (Variation ID: 237219).
GeneDx	RCV000487300	SCV000568718	uncertain significance	not provided	2016-05-02	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.98G>C at the cDNA level, p.Arg33Pro (R33P) at the protein level, and results in the change of an Arginine to a Proline (CGT>CCT). This variant was observed in at least one individual with early-onset colorectal cancer whose tumor was microsatellite stable (Pérez-Cabornero 2013). MSH6 Arg33Pro was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg33Pro occurs at a position that is not conserved and is not located in a known functional domain (Terui 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Arg33Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000575454	SCV000664865	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	The p.R33P variant (also known as c.98G>C), located in coding exon 1 of the MSH6 gene, results from a G to C substitution at nucleotide position 98. The arginine at codon 33 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in a 30-year-old individual diagnosed with microsatellite stable colorectal cancer who had no reported family history of cancer (Perez-Cabornero L et al. J Mol Diagn. 2013 May;15(3):380-90). 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.
Color Diagnostics, LLC DBA Color Health	RCV000575454	SCV000911681	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline 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 been reported in an individual with early-onset colorectal cancer with no other cancer history in the family (PMID: 23523604). The proband's tumor showed microsatellite stability. 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.
PreventionGenetics, part of Exact Sciences	RCV004532835	SCV004105278	uncertain significance	MSH6-related disorder	2023-01-30	criteria provided, single submitter	clinical testing	The MSH6 c.98G>C variant is predicted to result in the amino acid substitution p.Arg33Pro. This variant was reported in at least one individual with colorectal cancer (Pérez-Cabornero et al. 2013. PubMed ID: 23523604). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/237219/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003463645	SCV004195575	uncertain significance	Endometrial carcinoma	2023-08-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998735	SCV004827908	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline 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 been reported in an individual with early-onset colorectal cancer with no other cancer history in the family (PMID: 23523604). The proband's tumor showed microsatellite stability. 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.