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 colorectal neoplasms 2020-09-01 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage 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). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 22290698, 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487781 SCV000575206 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000213900 SCV000911850 benign Hereditary cancer-predisposing syndrome 2016-09-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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