ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4039G>C (p.Ala1347Pro) (rs730881809)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766290 SCV000211332 uncertain significance not provided 2015-10-23 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.4039G>C at the cDNA level, p.Ala1347Pro (A1347P) at the protein level, and results in the change of an Alanine to a Proline (GCT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala1347Pro 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 Alanine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Ala1347Pro occurs at a position that is not conserved and is located in an MSH2 binding site and within domain V of the MutS domain (Kariola 2002, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available information, it is unclear whether MSH6 Ala1347Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000229406 SCV000283840 uncertain significance Hereditary nonpolyposis colon cancer 2019-10-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 1347 of the MSH6 protein (p.Ala1347Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182650). 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, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160703 SCV000601601 uncertain significance not specified 2017-01-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000576090 SCV000670006 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000663168 SCV000786329 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-04-09 criteria provided, single submitter clinical testing
Color RCV000576090 SCV000908443 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000160703 SCV000966670 uncertain significance not specified 2018-10-17 criteria provided, single submitter clinical testing The p.Ala1347Pro variant in MSH6 has not been reported in the literature in indi viduals with MSH6-associated cancers, but has been reported by other clinical la boratories in ClinVar (Variation ID: 182650). This variant has also been identif ied in 1/111534 European chromosomes by gnomAD ( ). Computational prediction tools and conservation analysis suggest that the p.A la1347Pro variant may not impact the protein, though this information is not pre dictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala1347Pro variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2.

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