Submissions for variant NM_000179.3(MSH6):c.136G>A (p.Gly46Arg)

gnomAD frequency: 0.00001  dbSNP: rs863224616

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204112	SCV000259522	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 46 of the MSH6 protein (p.Gly46Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 22495361). ClinVar contains an entry for this variant (Variation ID: 219577). 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 with a negative predictive value of 95%. 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.
GeneDx	RCV000484712	SCV000566519	uncertain significance	not provided	2023-09-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colon cancer, whose tumor displayed normal mismatch repair immunohistochemistry (Okkels et al., 2012); This variant is associated with the following publications: (PMID: 22495361)
Ambry Genetics	RCV000561391	SCV000662356	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-15	criteria provided, single submitter	clinical testing	The p.G46R variant (also known as c.136G>A), located in coding exon 1 of the MSH6 gene, results from a G to A substitution at nucleotide position 136. The glycine at codon 46 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in a Danish individual with a personal and/or family history suspicious for Lynch syndrome whose tumor had normal immunohistochemistry (Okkels H et al. Appl. Immunohistochem. Mol. Morphol., 2012 Oct;20:470-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Counsyl	RCV000663157	SCV000786312	uncertain significance	Lynch syndrome 5	2018-04-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765676	SCV000897018	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000561391	SCV000911817	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 46 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 Lynch syndrome (PMID: 22495361). 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.
Myriad Genetics, Inc.	RCV000663157	SCV004018874	uncertain significance	Lynch syndrome 5	2023-03-28	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.
All of Us Research Program, National Institutes of Health	RCV003997571	SCV004828008	uncertain significance	Lynch syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 46 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 Hereditary nonpolyposis colorectal cancer (PMID: 22495361). 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.