Submissions for variant NM_000245.4(MET):c.1715G>A (p.Ser572Asn)

gnomAD frequency: 0.00188  dbSNP: rs199771406

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001507175	SCV000219083	benign	Renal cell carcinoma	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000168390	SCV000466445	benign	Papillary renal cell carcinoma type 1	2018-01-12	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.
Ambry Genetics	RCV000564000	SCV000664651	likely benign	Hereditary cancer-predisposing syndrome	2018-06-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000610933	SCV000727285	likely benign	not specified	2018-02-01	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.
Mendelics	RCV000168390	SCV001137453	likely benign	Papillary renal cell carcinoma type 1	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000610933	SCV001774633	benign	not specified	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: MET c.1715G>A (p.Ser572Asn) results in a conservative amino acid change located in the IPT domain (IPR002909) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 249370 control chromosomes. The observed variant frequency is approximately 334 fold of the estimated maximal expected allele frequency for a pathogenic variant in MET causing Papillary Renal Cell Carcinoma phenotype (1.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1715G>A in individuals affected with Papillary Renal Cell Carcinoma and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000564000	SCV002532109	likely benign	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000610933	SCV004025168	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843487	SCV002103104	uncertain significance	Hepatoblastoma		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003927559	SCV004745839	likely benign	MET-related disorder	2019-06-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).