ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2951A>C (p.Asn984Thr) (rs587779927)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115396 SCV000149305 uncertain significance not provided 2014-01-14 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2951A>C at the cDNA level, p.Asn984Thr (N984T) at the protein level, and results in the change of an Asparagine to a Threonine (AAT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asn984Thr 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. This variant is a conservative substitution of one neutral polar amino acid for another, altering a position that is only moderately conserved throughout evolution and is located in the MutS domain (Terui 2013). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Asn984Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000204834 SCV000261024 uncertain significance Hereditary nonpolyposis colon cancer 2019-06-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 984 of the MSH6 protein (p.Asn984Thr). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. ClinVar contains an entry for this variant (Variation ID: 127575). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000409319 SCV000489729 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV001017633 SCV001178742 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-02 criteria provided, single submitter clinical testing Insufficient evidence

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