ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.884+4A>G (rs267607777)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075907 SCV000106924 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant allele results in splicing abberation leading to premature stop codon: full inactivation of variant allele
Invitae RCV000630077 SCV000751033 pathogenic Hereditary nonpolyposis colon cancer 2019-09-10 criteria provided, single submitter clinical testing This sequence change falls in intron 10 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 reported in several individuals and families affected with colon cancer and/or Lynch syndrome (PMID: 25980754, 21239990, 17653898, 18561205), and has been reported to segregate with Lynch syndrome in at least one family (PMID: 17653898). This variant is also known as IVS10+4A>G. ClinVar contains an entry for this variant (Variation ID: 90414). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this sequence change results in skipping of exon 10 (PMID: 18561205, 17653898). This is predicted to result in a premature stop codon that may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001018387 SCV001179619 pathogenic Hereditary cancer-predisposing syndrome 2019-04-12 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Functionally-validated splicing mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.