ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.91G>A (p.Ala31Thr) (rs749671520)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487360 SCV000569949 uncertain significance not provided 2016-04-12 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.91G>A at the cDNA level, p.Ala31Thr (A31T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ala31Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ala31Thr occurs at a position that is conserved across species and is located within the MLH domain, as well as the ATP-binding and hydrolysis domain (Pang 1997, Raevaara 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Ala31Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569326 SCV000676040 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000765728 SCV000897096 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000816684 SCV000957202 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 31 of the MLH1 protein (p.Ala31Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 420921). 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. 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.

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