Submissions for variant NM_000179.3(MSH6):c.698C>G (p.Pro233Arg)

dbSNP: rs142949377

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131704	SCV000186742	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-25	criteria provided, single submitter	clinical testing	The p.P233R variant (also known as c.698C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 698. The proline at codon 233 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000212633	SCV000211260	uncertain significance	not provided	2018-06-14	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.698C>G at the cDNA level, p.Pro233Arg (P233R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). The variant was predicted by Terui et al. (2013) to have no impact on MSH6 based on a bioinformatics tool integrating in silico models with clinical and molecular data. MSH6 Pro233Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the nuclear localization signals (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Pro233Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000557767	SCV000624994	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-05-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131704	SCV000685516	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 233 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). Splice site prediction tools suggest that this variant may impact RNA splicing. 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 been identified in 1/250858 chromosomes 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.
Counsyl	RCV000663288	SCV000786530	uncertain significance	Lynch syndrome 5	2018-05-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663288	SCV004019046	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003467182	SCV004197715	uncertain significance	Endometrial carcinoma	2023-09-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998115	SCV004836841	uncertain significance	Lynch syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 233 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 been identified in 1/250858 chromosomes 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.