ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.314C>T (p.Ala105Val)

dbSNP: rs867655979
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001035346 SCV001198671 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-12 criteria provided, single submitter clinical testing 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. 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. 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. This variant has not been reported in the literature in individuals with MLH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 105 of the MLH1 protein (p.Ala105Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193810 SCV001362943 uncertain significance not specified 2019-02-08 criteria provided, single submitter clinical testing Variant summary: The variant, MLH1 c.314C>T (p.Ala105Val) results in a non-conservative amino acid change located in the Histidine kinase/HSP90-like ATPase domain and DNA mismatch repair protein family, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246162 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.314C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV002320232 SCV002610524 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-25 criteria provided, single submitter clinical testing The p.A105V variant (also known as c.314C>T), located in coding exon 4 of the MLH1 gene, results from a C to T substitution at nucleotide position 314. The alanine at codon 105 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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