ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.563C>T (p.Ala188Val) (rs777971431)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484514 SCV000568162 uncertain significance not provided 2017-02-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.563C>T at the cDNA level, p.Ala188Val (A188V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ala188Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ala188Val occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Ala188Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000542526 SCV000625178 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 188 of the MLH1 protein (p.Ala188Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs777971431, ExAC 0.03%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 419939). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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, 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.
Ambry Genetics RCV000574007 SCV000676038 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Color RCV000574007 SCV000684843 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing

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