ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.241G>A (p.Ala81Thr) (rs587779239)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074747 SCV000107956 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Ambry Genetics RCV000213900 SCV000273913 likely benign Hereditary cancer-predisposing syndrome 2018-12-24 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000627691 SCV000551067 uncertain significance Hereditary nonpolyposis colon cancer 2019-05-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 81 of the MSH6 protein (p.Ala81Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. While this variant is not present in population databases (rs587779239), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89282). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. However, these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487781 SCV000575206 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
Color RCV000213900 SCV000911850 benign Hereditary cancer-predisposing syndrome 2016-09-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780462 SCV000917729 uncertain significance not specified 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.241G>A (p.Ala81Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/30778 control chromosomes in gnomAD at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).

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