ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.197C>A (p.Pro66Gln) (rs730881812)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160710 SCV000211341 uncertain significance not provided 2014-08-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.197C>A at the cDNA level, p.Pro66Gln (P66Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Pro66Gln 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 Proline and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Pro66Gln occurs at a position that is variable across species and is not located in a known functional domain. 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 Pro66Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573868 SCV000669957 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000811656 SCV000951933 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 66 of the MSH6 protein (p.Pro66Gln). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and glutamine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 182655). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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