ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2103G>A (p.Gln701=) (rs63750603)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075533 SCV000106530 uncertain significance Lynch syndrome I 2018-06-13 reviewed by expert panel curation Criteria changed for variants in last base of exon therefore downgrade classification
Invitae RCV000629835 SCV000750791 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-05-03 criteria provided, single submitter clinical testing This sequence change affects codon 701 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. This variant also falls at the last nucleotide of exon 18 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 90048). 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 results in altered mRNA splicing that skips exon 18 (PMID: 26247049). A different variant affecting this nucleotide (c.2103G>C) has been determined to be pathogenic (PMID: 21404177, 16341550). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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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