ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.928A>G (p.Thr310Ala) (rs779581111)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234748 SCV000284082 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 310 of the MLH1 protein (p.Thr310Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs779581111, ExAC 0.03%). This variant has not been reported in the literature in individuals with a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 237351). 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, this variant has uncertain impact on MLH1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000759816 SCV000618479 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.928A>G at the cDNA level, p.Thr310Ala (T310A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Thr310Ala was observed at an allele frequency of 0.02% (3/11578) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Thr310Ala occurs at a position that is conserved across species and is located within the N-terminal ATPase domain (Andersen 2012). 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 Thr310Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000581030 SCV000684883 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759816 SCV000889410 uncertain significance not provided 2017-10-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780417 SCV000917649 uncertain significance not specified 2017-09-12 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.928A>G (p.Thr310Ala) variant located in the Ribosomal protein S5 domain 2-type fold (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have not been validated by functional studies. This variant was found in 6/246186 control chromosomes at a frequency of 0.0000244, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. A clinical diagnostic laboratory classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

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