Submissions for variant NM_000179.3(MSH6):c.2195G>A (p.Arg732Gln)

dbSNP: rs749746725

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223534	SCV000279763	uncertain significance	not provided	2017-05-15	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2195G>A at the cDNA level, p.Arg732Gln (R732Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature a germline variant; however, it has been reported as a somatic variant in a colorectal tumor (Vasovcak 2012). MSH6 Arg732Gln was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Arg732Gln occurs at a position that is conserved across species and is located in the lever domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg732Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000532996	SCV000624733	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564357	SCV000662445	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	The p.R732Q variant (also known as c.2195G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2195. The arginine at codon 732 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in a patient diagnosed with breast cancer at age 44 and colon cancer at age 49 (Dominguez-Valentin M et al. BMC Med. Genet. 2018 Feb;19:26). Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as an uncertain variant (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). 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.
Color Diagnostics, LLC DBA Color Health	RCV000564357	SCV000685264	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 732 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual in a cohort of Norwegian individuals affected with familial colorectal cancer (PMID: 29458332). This variant has been identified in 1/250880 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758666	SCV000887437	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.2195G>A has a 34.3% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
All of Us Research Program, National Institutes of Health	RCV000758666	SCV004836196	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 732 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual in a cohort of Norwegian individuals affected with familial colorectal cancer (PMID: 29458332). This variant has been identified in 1/250880 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.