Submissions for variant NM_000179.3(MSH6):c.821G>A (p.Ser274Asn)

gnomAD frequency: 0.00001  dbSNP: rs587779949

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115444	SCV000149353	uncertain significance	not provided	2014-02-25	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.821G>A at the cDNA level, p.Ser274Asn (S274N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser274Asn 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. This variant is a conservative substitution of one neutral polar amino acid for another, altering a position that is well conserved throughout evolution and is not located within a known functional domain but does undergo phosphorylation (UniProt). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Ser274Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000222274	SCV000277164	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-23	criteria provided, single submitter	clinical testing	The p.S274N variant (also known as c.821G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 821. The serine at codon 274 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well 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.
Invitae	RCV000554997	SCV000625006	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222274	SCV000904016	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 274 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 4/251032 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115444	SCV004222060	uncertain significance	not provided	2022-11-25	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00012 (4/34584 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a somatic variant detected in a colorectal cancer tumor (PMID: 31104363 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997257	SCV004839272	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 274 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 not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251032 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.