ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.67G>C (p.Ala23Pro) (rs730881810)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482378 SCV000566690 uncertain significance not provided 2015-05-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.67G>C at the cDNA level, p.Ala23Pro (A23P) at the protein level, and results in the change of an Alanine to a Proline (GCC>CCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala23Pro 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 Ala23Pro occurs at a position that is not conserved and is not located in a known functional domain (Terui 2013). 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 Ala23Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000537973 SCV000624992 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 23 of the MSH6 protein (p.Ala23Pro). 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 MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 419112). 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.
Ambry Genetics RCV000565704 SCV000669924 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-26 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000565704 SCV000903628 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing

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