ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1A>G (p.Met1Val) (rs587778967)

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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) RCV000075477 SCV000106473 pathogenic Lynch syndrome I 2017-06-30 reviewed by expert panel curation MLH1 initiation codon variant
Invitae RCV000629832 SCV000750788 pathogenic Hereditary nonpolyposis colon cancer 2018-04-16 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the MLH1 mRNA. The next in-frame methionine is located at codon 35. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome (PMID: 24302565, 11112663) and colorectal cancer (PMID: 28944238). ClinVar contains an entry for this variant (Variation ID: 89994). Experimental studies have shown that this variant significantly reduces protein expression, likely affecting translation initiation (PMID: 24302565). The next in-frame methionine is found at codon 35, and experimental studies demonstrate that this alternate start codon produces protein levels comparable to the wild-type allele. However, the functional capacity of the variant protein missing the first 34 amino acids is equivalent to known MMR deficient variants, suggesting that the first 34 amino acids are critical for normal protein function (PMID: 24302565). For these reasons, this variant has been classified as Pathogenic.

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