ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2104-1_2104delinsTCTTATGACATCTAAT (rs1553665467)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000538907 SCV000625128 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-04-28 criteria provided, single submitter clinical testing This sequence change removes two nucleotides and inserts 16 nucleotides in the splice acceptor site of the last intron of the MLH1 mRNA (c.2104-1_2104delinsTCTTATGACATCTAAT). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt normal splicing of the last exon of the MLH1 mRNA, and likely disrupts the last 55 amino acids of the MLH1 protein. This particular variant has not been reported in the literature in individuals with an MLH1-related disease. This variant likely disrupts the highly conserved C-terminal domain (CTD), which is responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). Also, different truncations downstream of this variant (p.Tyr750*, p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 24802709, 8797773, 27295708, 18566915, 18931482 and Invitae database). This suggests that deletion of this region of the MLH1 protein is causative of disease. In summary, this variant is a novel change that is expected to disrupt the normal structure and function of the MLH1 protein. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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