Submissions for variant NM_000179.3(MSH6):c.644T>G (p.Val215Gly)

gnomAD frequency: 0.00001  dbSNP: rs587779946

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115437	SCV000149346	uncertain significance	not provided	2018-01-12	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.644T>G at the cDNA level, p.Val215Gly (V215G) at the protein level, and results in the change of a Valine to a Glycine (GTA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Val215Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located 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 Val215Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001071512	SCV001236820	benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001190341	SCV001357801	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 215 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 colorectal cancer (PMID: 30521064), who also carried a variant in the MSH6 gene, c.3226C>T (p.R1076C), that has been described as likely pathogenic (ClinVar Variation ID: 89357) and could explain the observed phenotype. This variant has been identified in 2/247028 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.
Ambry Genetics	RCV001190341	SCV002657463	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-22	criteria provided, single submitter	clinical testing	The p.V215G variant (also known as c.644T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 644. The valine at codon 215 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in a 66-year-old male diagnosed with colorectal cancer, whose tumor showed loss of the MSH6 protein on immunohistochemistry (IHC) (Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This variant was also detected in a cohort of 8085 consecutive Chinese breast cancer patients (Hu L et al. NPJ Breast Cancer, 2022 Apr;8:52). This amino acid position is poorly 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.
Baylor Genetics	RCV003467043	SCV004197652	uncertain significance	Endometrial carcinoma	2023-10-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997254	SCV004841171	uncertain significance	Lynch syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 215 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 colorectal cancer (PMID: 30521064), who also carried a variant in the MSH6 gene, c.3226C>T (p.R1076C), that has been described as likely pathogenic (ClinVar Variation ID: 89357) and could explain the observed phenotype. This variant has been identified in 2/247028 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.