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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met324Leufs*20) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). 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 and c.1024_1038+1del 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001017049 SCV001178072 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-18 criteria provided, single submitter clinical testing <span style="font-family:arial,helvetica,sans-serif; font-size:12px">The c.1024_1038+1del16<span style="font-family:arial,helvetica,sans-serif; font-size:12px"> intronic<span style="font-family:arial,helvetica,sans-serif; font-size:12px"> alteration results from a deletion of 16 nucleotides starting 15 nucleotides upstream from the end of coding exon 11 and including the first nucleotide of intron 11 of the MLH1 gene. This alteration has been detected in multiple families meeting Amsterdam Criteria and has co-segregated with colon cancer in one member from one of these families; however, immunohistochemistry and microsatellite instability results from these tumors were not always consistent with MLH1-related disease (Pino MS. J Mol Diagn. 2009 May;11(3):238-47; Cruz-Correa M. Fam. Cancer. 2015 Sep;14(3):415-25; Ambry internal data). Using the BDGP and ESEfinder splice site prediction tools, the strength of the native donor splice site is maintained, however, it is predicted that the donor site will use one nucleotide from the remaining coding sequence leading to a predicted frameshift and either an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV001017049 SCV001356162 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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