ClinVar Miner

Submissions for variant NM_001167617.2(MLH1):c.-134del (rs63750028)

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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) RCV000075267 SCV000106261 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000213962 SCV000276778 pathogenic Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing The c.156delA pathogenic mutation, located in coding exon 2 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 156, causing a translational frameshift with a predicted alternate stop codon (p.E53Rfs*4). 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.
Invitae RCV000533345 SCV000625082 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu53Argfs*4) 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 an individual undergoing multi-gene panel testing (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 89793). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000075267 SCV000696118 likely pathogenic Lynch syndrome 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.156delA (p.Glu53Argfs) 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.Leu404fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121360 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV001027534 SCV001161674 pathogenic Lynch syndrome II 2019-08-23 criteria provided, single submitter clinical testing The heterozygous deletion c.156delA (p.Glu53ArgfsTer4) lies in exon 2 of the MLH1 gene and is predicted to cause a frameshift and consequent premature termination of the protein. The resultant protein is likely to lack the major functional domains of the protein, this will likely result in loss of function. The variant has been reported in the ClinVar database as pathogenic. The variant has been previously reported in patients affected with Lynch Syndrome and it is indicated to be disease causing. In summary, the variant meets our criteria to be classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000582660 SCV000691841 likely pathogenic not provided no assertion criteria provided clinical testing

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