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

dbSNP: rs863224616

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197947	SCV000254275	likely benign	Hereditary nonpolyposis colorectal neoplasms	2022-12-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575386	SCV000670029	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The p.G46R variant (also known as c.136G>C), located in coding exon 1 of the MSH6 gene, results from a G to C 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 immunohistochemical results (Okkels H et al. Appl. Immunohistochem. Mol. Morphol., 2012 Oct;20:470-7). This alteration was also identified in an Asian individual with a personal history of breast cancer at age 28 who had family history of lymphoma and prostate cancer (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000765677	SCV000897019	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	RCV000575386	SCV001353861	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-07	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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/217728 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.
All of Us Research Program, National Institutes of Health	RCV003996993	SCV004828019	uncertain significance	Lynch syndrome	2024-01-11	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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/217728 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000575386	SCV005045438	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-05	criteria provided, single submitter	clinical testing