ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.34C>A (p.Pro12Thr) (rs587782084)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130582 SCV000185454 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000484580 SCV000572676 uncertain significance not provided 2017-01-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.34C>A at the cDNA level, p.Pro12Thr (P12T) at the protein level, and results in the change of a Proline to a Threonine (CCC>ACC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Pro12Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Pro12Thr occurs at a position that is conserved in mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Pro12Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000530606 SCV000624875 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 12 of the MSH6 protein (p.Pro12Thr). The proline residue is weakly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs587782084, ExAC 0.005%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 141885). 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. 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.
Mendelics RCV000708849 SCV000837861 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000130582 SCV000903275 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing

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