Submissions for variant NM_000179.3(MSH6):c.1376C>G (p.Ser459Cys)

gnomAD frequency: 0.00001  dbSNP: rs587782346

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131285	SCV000186255	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-23	criteria provided, single submitter	clinical testing	The p.S459C variant (also known as c.1376C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1376. The serine at codon 459 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was detected in 1/91 Irish patients with histologically confirmed breast cancer and 0/77 ethnically matched controls (McVeigh ÚM et al. Ir J Med Sci, 2020 Aug;189:849-864). 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.
GeneDx	RCV000479474	SCV000571856	uncertain significance	not provided	2016-09-30	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1376C>G at the cDNA level, p.Ser459Cys (S459C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser459Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser459Cys occurs at a position that is conserved across species and is located in the binding sites of MSH2 and the MutS domain I (Kariola 2002, Terui 2013). 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 Ser459Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000548616	SCV000624644	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-09-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131285	SCV000685189	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 459 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/282508 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509239	SCV002819651	uncertain significance	not specified	2022-12-19	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1376C>G (p.Ser459Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251100 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1376C>G has been reported in the literature in one individual affected with breast cancer (McVeigh_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998097	SCV004841339	uncertain significance	Lynch syndrome	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 459 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/282508 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.