ClinVar Miner

Submissions for variant NM_001127500.3(MET):c.1039G>A (p.Ala347Thr) (rs200074800)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119117 SCV000153830 likely benign Renal cell carcinoma, papillary, 1 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000119117 SCV000466434 benign Renal cell carcinoma, papillary, 1 2018-01-13 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 RCV000657129 SCV000569718 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing This variant is denoted MET c.1039G>A at the cDNA level, p.Ala347Thr (A347T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). MET Ala347Thr was observed in one individual with non-small cell lung cancer and at least one other with an advanced cancer of unspecified histology (Sattler 2011, Mandelker 2017). This variant was also identified in an individual undergoing whole exome sequencing, who was not reported to have a personal or family history of cancer (Gonzalez-Garay 2013), and in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in Bodian 2014 were younger than 50 years old thus the unaffected status of this individual may not be significant. On functional interrogation, Krishnaswamy et al. (2009) showed MET Ala347Thr to have similar hepatocyte growth factor ligand binding as the wild type protein. MET Ala347Thr was observed at an allele frequency of 0.09% (111/124,006) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the Sema and extracellular domains (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MET Ala347Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance
Ambry Genetics RCV000567774 SCV000673685 likely benign Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Other data supporting benign classification;Subpopulation frequency in support of benign classification
Mendelics RCV000119117 SCV000838244 uncertain significance Renal cell carcinoma, papillary, 1 2018-07-02 criteria provided, single submitter clinical testing
ITMI RCV000121345 SCV000085522 not provided not specified 2013-09-19 no assertion provided reference population

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