ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.208-?_306+?del

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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) RCV000075518 SCV000106507 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research In frame large deletion interrupting functional domain
Invitae RCV000459146 SCV000563810 pathogenic Lynch syndrome 2016-09-30 criteria provided, single submitter clinical testing This variant is a gross deletion of the genomic region encompassing exon 3 of the MLH1 gene. This leads to an in-frame deletion, preserving the integrity of the reading frame. Similar in-frame deletions of exon 3 have been reported in two affected family members with Lynch syndrome, and in an individual affected with endometrial cancer (PMID: 8993976, 24323032). This in-frame deletion is expected to remove 33 amino acids (residues 70-102) from the ATPase domain of the MLH1 protein (PMID: 22753075). The deleted region contains conserved amino acids involved in ATP binding and hydrolysis, which are important for the mismatch repair activity of the MLH1 protein (PMID: 15475387, 11793442, 10199405, 9482749). For these reasons, this variant has been classified as Pathogenic.

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