ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.680G>A (p.Ser227Asn) (rs587779317)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160654 SCV000211259 uncertain significance not provided 2015-11-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.680G>A at the cDNA level, p.Ser227Asn (S227N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser227Asn 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 Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ser227Asn occurs at a position that is conserved among mammals and is not located in a known functional domain (UniProt, Terui 2013). In addition, in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Ser227Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000220490 SCV000273534 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000545909 SCV000624993 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 227 of the MSH6 protein (p.Ser227Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with an MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182610). 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, this variant has uncertain impact on MSH6 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000780484 SCV000917774 uncertain significance not specified 2018-08-27 criteria provided, single submitter clinical testing Variant summary: MSH6 c.680G>A (p.Ser227Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245144 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.680G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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