ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2253del (p.Val752fs) (rs267607901)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000701901 SCV000830724 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-05-10 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 19 of the MLH1 mRNA (c.2253delA), causing a frameshift at codon 752. This is expected to replace the last five amino acids of the MLH1 protein with 30 random amino acids, creating a new downstream translational stop signal that extends the length of the protein by 25 amino acids. While this is not anticipated to result in nonsense mediated decay, it is expected to result in a disrupted MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. While no functional studies have been performed to test the effect of this particular variant on MLH1 protein function or stability, it affects the highly conserved C-terminal domain (CTD) responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). Different frameshift variants including c.2269dup, located downstream of this variant have been determined to be pathogenic (PMID: 8128251, 9697702, 12810663, 14985405, Invitae). This suggests that disruption of this region of the MLH1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001014945 SCV001175721 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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