ClinVar Miner

Submissions for variant NM_000245.4(MET):c.2975C>T (p.Thr992Ile)

gnomAD frequency: 0.00911  dbSNP: rs56391007
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Total submissions: 27
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000121340 SCV000111370 benign not specified 2018-03-26 criteria provided, single submitter clinical testing
Invitae RCV001507182 SCV000166422 benign Renal cell carcinoma 2021-12-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163261 SCV000213789 benign Hereditary cancer-predisposing syndrome 2014-11-20 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203290 SCV000258327 uncertain significance Congenital diaphragmatic hernia 2015-03-03 criteria provided, single submitter research It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family.
Vantari Genetics RCV000163261 SCV000267045 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121340 SCV000306712 likely benign not specified criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000123120 SCV000466455 benign Renal cell carcinoma, papillary, 1 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx RCV000121340 SCV000518950 benign not specified 2017-03-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034529 SCV000697659 benign not provided 2016-08-18 criteria provided, single submitter clinical testing Variant summary: The c.3029C>T (p.Thr1010Ile) in MET gene is a missense change that involves a conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant falls into c-MET JM domain that regulates cytoskeletal functions: adhesion, motility, and migration and Mutation in this domain were shown to enhance lung cancer tumorigenicity in vitro. The variant is present in the control population dataset of ExAC and published general population data at an overall frequency 0.008 (962/1217700 chrs tested) including 6 homozygotes. It has particularly higher frequency in African subpopulation with an allele frequency of 2% (134/6576 chromosomes). These frequencies exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000015). The variant has been reported in healthy individuals and metastatic breast cancer, lung cancer and colorectal cancer patients (Liu_2015, Agrawal_2015). However, it has not been associated with increased risk for developing breast cancer in large genome wide association studies and previous laboratory studies have reported conflicting functional effects for the T1010I variant in NIH3T3 fibroblast and murine myeloid BA/F3 cell line models as discussed by Liu et al (Agrawal_2015). The variant is reported as Benign/VUS/Functional Polymorphism by a multiple reputable databases/clinical laboratories and published reports. Taken together, the variant was classified as Benign.
Mendelics RCV000123120 SCV000838268 benign Renal cell carcinoma, papillary, 1 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000034529 SCV001144504 benign not provided 2019-07-18 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000034529 SCV001155233 likely benign not provided 2019-04-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034529 SCV001156913 benign not provided 2020-06-29 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000123120 SCV001775505 benign Renal cell carcinoma, papillary, 1 2021-03-17 criteria provided, single submitter clinical testing The MET c.3029C>T (p.Thr1010Ile) missense change is present at a maximum non-founder subpopulation frequency of 1.2% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-116411990-C-T?dataset=gnomad_r2_1). This population frequency is higher than expected for a pathogenic variant in MET causing predisposition to hereditary papillary renal cell carcinoma (BS1). This variant has also been reported as homozygous 13 times in the gnomAD v2.1.1 database which suggests that this is a benign polymorphism (BS2). In silico tools are not in agreement about the effect on the gene or protein function, and functional studies have reported conflicting effects in cell line models (PMIDs: 14559814, 25605252). This variant has been identified in individuals with colorectal cancer (PMID: 21970370), metastatic breast cancer (PMID: 25605252), and those without a personal or family history of hereditary papillary renal cell carcinoma (internal data). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria: BS1, BS2.
Genetic Services Laboratory,University of Chicago RCV000121340 SCV002069849 benign not specified 2021-03-29 criteria provided, single submitter clinical testing
Pathology Department,Puerta del Mar University Hospital RCV002227927 SCV002507276 uncertain significance Classic Hodgkin lymphoma 2021-10-01 criteria provided, single submitter research
Sema4,Sema4 RCV000163261 SCV002532142 benign Hereditary cancer-predisposing syndrome 2020-07-20 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034529 SCV000043315 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121340 SCV000085515 not provided not specified 2013-09-19 no assertion provided reference population
Database of Curated Mutations (DoCM) RCV000421063 SCV000505272 likely pathogenic Carcinoma 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431770 SCV000505273 likely pathogenic Neoplasm 2014-12-26 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000034529 SCV001740404 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000121340 SCV001807787 benign not specified no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000034529 SCV001917902 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000121340 SCV001930924 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000121340 SCV001952745 benign not specified no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000121340 SCV002550812 benign not specified 2021-09-10 no assertion criteria provided clinical testing

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