Submissions for variant NM_000179.3(MSH6):c.1046A>G (p.Gln349Arg)

dbSNP: rs869312797

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210099	SCV000266198	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220598	SCV000275964	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-01	criteria provided, single submitter	clinical testing	The p.Q349R variant (also known as c.1046A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1046. The glutamine at codon 349 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in an individual with colon cancer at age 40y and a family history of colon cancer (Shirts BH et al. Genet. Med. 2016 Oct;18:974-81). This amino acid position is well 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.
Invitae	RCV000524098	SCV000283695	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-03	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. ClinVar contains an entry for this variant (Variation ID: 224578). This missense change has been observed in individual(s) with colon cancer (PMID: 26845104). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 349 of the MSH6 protein (p.Gln349Arg).
GeneDx	RCV000523088	SCV000616789	uncertain significance	not provided	2019-07-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26845104)
Color Diagnostics, LLC DBA Color Health	RCV000220598	SCV000908368	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 349 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 affected with colon cancer (PMID: 26845104). 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.