ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2479A>G (p.Asn827Asp) (rs878853716)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231716 SCV000283752 uncertain significance Hereditary nonpolyposis colon cancer 2017-10-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 827 of the MSH6 protein (p.Asn827Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 237158). 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: "Possibly 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.
GeneDx RCV000483224 SCV000565225 uncertain significance not provided 2015-02-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2479A>G at the cDNA level, p.Asn827Asp (N827D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asn827Asp 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 Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Asn827Asp occurs at a position that is conserved across mammals and is located in the ATPase domain (Lutzen 2008). 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 Asn827Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000490886 SCV000580207 likely benign Hereditary cancer-predisposing syndrome 2016-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign)
Color RCV000490886 SCV000905508 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing

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