ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1989+5G>C (rs267607878)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000075459 SCV000887327 pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1989+5G>C has a 99.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Invitae RCV001040247 SCV001203809 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-06-01 criteria provided, single submitter clinical testing This sequence change falls in intron 17 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an a family affected with Lynch syndrome (PMID: 8993976, 14970868). This variant is also known as IVS17+5G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 899776). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 8993976). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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