ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2259del (p.Phe753fs) (rs1060500698)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463125 SCV000543588 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-05-12 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 19 of the MLH1 mRNA (c.2259delT), causing a frameshift at codon 753. This is expected to replace the last 4 amino acids of the MLH1 protein with 29 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 been reported in a family affected with hereditary non polyposis colorectal cancer (HNPCC) (PMID: 21901500). ClinVar contains an entry for this variant (Variation ID: 405405). 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 RCV001014958 SCV001175734 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Structural Evidence

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