ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.821G>A (p.Ser274Asn) (rs587779949)

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Total submissions: 4
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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 2017-11-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000554997 SCV000625006 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 274 of the MSH6 protein (p.Ser274Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs587779949, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127606). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000222274 SCV000904016 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing

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