Submissions for variant NM_000179.3(MSH6):c.1382T>G (p.Phe461Cys)

dbSNP: rs1064793187

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000477991	SCV000565215	uncertain significance	not provided	2015-01-29	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1382T>G at the cDNA level, p.Phe461Cys (F461C) at the protein level, and results in the change of a Phenylalanine to a Cysteine (TTT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Phe461Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Phenylalanine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Phe461Cys occurs at a position that is highly conserved across species and is located in the binding sites of MSH2 (Kariola 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider MSH6 Phe461Cys to be a variant of uncertain significance.
Ambry Genetics	RCV000564326	SCV000670107	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	clinical testing	The p.F461C variant (also known as c.1382T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 1382. The phenylalanine at codon 461 is replaced by cysteine, an amino acid with highly dissimilar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815191	SCV000955639	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 461 of the MSH6 protein (p.Phe461Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 418323). 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 expected to disrupt MSH6 protein function. 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.
Baylor Genetics	RCV004568145	SCV005054827	uncertain significance	Endometrial carcinoma	2024-03-24	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000477991	SCV005199198	uncertain significance	not provided	2022-10-11	criteria provided, single submitter	clinical testing