ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1989G>A (p.Glu663=) (rs63751662)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680174 SCV000106458 pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation RNA studies showed loss of the c.1989A allele in the cDNA, supporting the full splicing effect of the variant leading to p.Glu633_Glu663del.
Invitae RCV000075461 SCV000284041 likely pathogenic Hereditary nonpolyposis colon cancer 2018-02-23 criteria provided, single submitter clinical testing This sequence change affects codon 663 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. It also falls at the last nucleotide of exon 17 of the MLH1 coding sequence. This variant is not present in population databases (rs63751662, ExAC no frequency). This variant has been reported in individuals and a family affected with Lynch syndrome or colorectal cancer (PMID: 11208710, 19419416, 21615986, 27601186). ClinVar contains an entry for this variant (Variation ID: 89979). 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. A different variant affecting this nucleotide (c.1989G>T) has been determined to be likely pathogenic (PMID: 10480359, 16395668, 18561205, 21642682, 24278394, 21404117). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508038 SCV000601377 likely pathogenic not provided 2016-09-09 criteria provided, single submitter clinical testing

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