ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.347delC (p.Thr116Lysfs) (rs876661159)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223327 SCV000279683 pathogenic not provided 2015-12-14 criteria provided, single submitter clinical testing This deletion of one nucleotide in MLH1 is denoted c.347delC at the cDNA level and p.Thr116LysfsX20(T116KfsX20) at the protein level. The normal sequence, with the base that is deleted in braces, is ATTA[C]AACG. The deletion causes a frameshift, which changes a Threonine to a Lysine at codon 116, and creates a premature stop codon at position 20 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587441 SCV000696162 likely pathogenic Lynch syndrome 2017-04-12 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.347delC (p.Thr116Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1210_1211delCT, p.Leu404fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121410 control chromosomes. In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.

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