ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.241A>G (p.Thr81Ala) (rs786203745)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167181 SCV000218017 uncertain significance Hereditary cancer-predisposing syndrome 2014-12-15 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
GeneDx RCV000483321 SCV000567011 uncertain significance not provided 2015-06-25 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.241A>G at the cDNA level, p.Thr81Ala (T81A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Thr81Ala 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 Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Thr81Ala occurs at a position that is conserved across species and is located in the ATPase domain (Hardt 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Thr81Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001043997 SCV001207769 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 81 of the MLH1 protein (p.Thr81Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 187452). 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 disruptive, but these predictions have not been confirmed by published functional studies and their 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.
Color RCV000167181 SCV001340140 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-27 criteria provided, single submitter clinical testing

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