ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.104C>T (p.Ala35Val) (rs776547943)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461408 SCV000551111 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 35 of the MSH6 protein (p.Ala35Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs776547943, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 410435). 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.
GeneDx RCV000480657 SCV000567603 uncertain significance not provided 2015-08-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.104C>T at the cDNA level, p.Ala35Val (A35V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala35Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ala35Val occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002). 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 Ala35Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573037 SCV000662364 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000765675 SCV000897017 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000573037 SCV000908335 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing

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