ClinVar Miner

Submissions for variant NM_001354621.1(MLH1):c.-13dup (rs63750677)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075073 SCV000106062 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000791451 SCV000255266 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-14 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 11 of the MLH1 mRNA (c.1011dupC), causing a frameshift at codon 338. This creates a premature translational stop signal (p.Asn338Glnfs*24) and is expected to result in an absent or disrupted protein product. Truncating variants in MLH1 are known to be pathogenic. This particular truncation has been reported in the literature (PMID: 19459153, 9833759). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000478965 SCV000565149 pathogenic not provided 2018-04-12 criteria provided, single submitter clinical testing This duplication of one nucleotide in MLH1 is denoted c.1011dupC at the cDNA level and p.Asn338GlnfsX24 (N338QfsX24) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GCTC[dupC]AATT. The duplication causes a frameshift, which changes an Asparagine to a Glutamine at codon 338, and creates a premature stop codon at position 24 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MLH1 c.1011dupC, previously published as MLH1 1011insC, has been observed in at least two families meeting Amsterdam criteria for Lynch syndrome (Hutter 1998, Chong 2009). We consider this variant to be pathogenic.
Counsyl RCV000576465 SCV000677788 pathogenic Lynch syndrome II 2017-03-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000075073 SCV000917638 likely pathogenic Lynch syndrome 2017-10-13 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1011dupC (p.Asn338GlnfsX24) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1210_1211delCT, p.Leu404fsX12; c.1219C>T, p.Gln407X; c.1381A>T, p.Lys461X). One in silico tool predicts a damaging outcome for this variant. This variant was found in multiple patients with Lynch syndrome (Bonadona_2011, Chong_2009, Hutter_1998). This variant was found in 1/246092 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Ambry Genetics RCV001016999 SCV001178017 pathogenic Hereditary cancer-predisposing syndrome 2018-11-30 criteria provided, single submitter clinical testing The c.1011dupC pathogenic mutation, located in coding exon 11 of the MLH1 gene, results from a duplication of C at nucleotide position 1011, causing a translational frameshift with a predicted alternate stop codon (p.N338Qfs*24). This alteration was previously identified in two families fulfilling Amsterdam criteria for Lynch syndrome (Hutter P et al. Int. J. Cancer 1998 Dec;78(6):680-4; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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