ClinVar Miner

Submissions for variant NM_001258271.1(MLH1):c.1896+875_1896+882dup (rs1064794331)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478853 SCV000568870 likely pathogenic not provided 2015-11-18 criteria provided, single submitter clinical testing This duplication of 8 nucleotides in MLH1 is denoted c.1938_1945dupTGTGCCCC at the cDNA level and p.Pro649LeufsX15(P649LfsX15) at the protein level. The normal sequence, with the bases that are duplicated in braces, is ACTA[TGTGCCCC]CTTT. The duplication causes a frameshift, which changes a Proline to a Leucine at codon 649, and creates a premature stop codon at position 15 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. Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Invitae RCV000823748 SCV000964618 pathogenic Hereditary nonpolyposis colon cancer 2018-11-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro649Leufs*15) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 420181). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.

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