ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.588+5G>C (rs267607768)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000075775 SCV000837998 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075775 SCV000914316 uncertain significance Lynch syndrome 2019-01-30 criteria provided, single submitter research
Mendelics RCV000987153 SCV001136379 uncertain significance Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001045347 SCV001209189 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-07 criteria provided, single submitter clinical testing This sequence change falls in intron 7 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 individual(s) with Lynch syndrome (PMID: 18389388, 26437257). ClinVar contains an entry for this variant (Variation ID: 90286). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the c.588+5 nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15713769, 16341550, 18561205, 24090359, 17576681, 9536098). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. 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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