ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3259C>A (p.Pro1087Thr) (rs63750998)

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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 RCV000131160 SCV000186104 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000212679 SCV000211317 uncertain significance not provided 2018-05-07 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3259C>A at the cDNA level, p.Pro1087Thr (P1087T) at the protein level, and results in the change of a Proline to a Threonine (CCC>ACC). This variant was seen in a patient with a personal and family history of colorectal cancer and was absent in 189 healthy controls (Kolodner 1999); however, functional in vitro studies by Kariola et al. (2002) showed that this variant retains MSH2-MSH6 interaction and is MMR repair proficient. MSH6 Pro1087Thr was observed at an allele frequency of 0.04% (6/16510) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Pro1087Thr occurs at a position that is not conserved and is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Pro1087Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001083021 SCV000219165 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000131160 SCV000685376 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001137558 SCV001297510 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-10-13 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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