ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.63C>G (p.Asn21Lys) (rs876660097)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216301 SCV000277234 likely benign Hereditary cancer-predisposing syndrome 2016-08-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
GeneDx RCV000479204 SCV000568009 uncertain significance not provided 2015-09-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.63C>G at the cDNA level, p.Asn21Lys (N21K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asn21Lys 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 Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Asn21Lys occurs at a position that is not conserved and is not located in a known functional domain (Terui 2013, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH6 Asn21Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000814244 SCV000954646 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 21 of the MSH6 protein (p.Asn21Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 232956). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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