Submissions for variant NM_000179.3(MSH6):c.1480G>T (p.Ala494Ser)

dbSNP: rs758699749

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002230121	SCV000551214	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776440	SCV000911933	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 494 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 hereditary cancer in the literature. This variant has been identified in 1/251208 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	RCV000776440	SCV001172168	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.A494S variant (also known as c.1480G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 1480. The alanine at codon 494 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV003446065	SCV004171946	uncertain significance	Lynch syndrome 5		criteria provided, single submitter	clinical testing	The missense c.1480G>T (p.Ala494Ser) variant in MSH6 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala494Ser variant has allele frequency 0.0004% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely benign / Uncertain Significance. The amino acid change p.Ala494Ser in MSH6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Ala494Ser variant is novel (not in any individuals) in 1000 Genomes. The amino acid Ala at position 494 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
GenomeConnect, ClinGen	RCV002508935	SCV002818445	not provided	Lynch syndrome		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 05-21-2019 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.