Description
Variant summary: MLH1 c.1517T>C (p.Val506Ala) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-06 in 261636 control chromosomes (gnomAD). c.1517T>C has been reported in multiple colorectal cancer patients from families fulfilling the Amsterdam and the revised Bethesda criteria (e.g. Liu_1996, Chao_2008, Yurgelun_2015, Syngal_1999, Medeiros_2012). These data indicate that the variant is likely to be associated with disease. In in vitro functional studies, the variant showed reduced MLH1 expression and altered binding to PMS2 and EXO1, but mismatch repair (MMR) activity close to wild type (Shimodaira_1998, Guerrette_1999, Takahashi_2007, Hinrichsen_2013). Eight (other) submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=7) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |