ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1024_1038+1del (rs1553648201)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586802 SCV000696090 pathogenic Lynch syndrome 2016-11-21 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1024_1038+1delATGTACTTCACCCAGG variant involves the deletion of 16 nucleotides around the exon/intron 11 border. Mutation taster predicts a damaging outcome for this substitution while 5/5 splice site tools predicts the variant to create a splice site at nucleotide 1023. The aberrant splicing product is predicted to result in an in-frame deletion p.Met342_Gln346del deletion (Alamut). This variant is absent in 120030 control chromosomes. It was reported in multiple LS patients (Pino_2009, Cruz-Correa_2015) and at least one family, it was shown to co-segregate with the disease in two affected family members, strongly supporting for causality. Taken together, this variant is classified as pathogenic.
Invitae RCV000791474 SCV000930725 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-29 criteria provided, single submitter clinical testing This variant results in the deletion of part of exon 11 (c.1024_1038+1del) of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 19324997, 25782445, Invitae). This variant is also known as c.1024del16 in the literature. ClinVar contains an entry for this variant (Variation ID: 495757). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV001017049 SCV001178072 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-18 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Color RCV001017049 SCV001356162 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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