Submissions for variant NM_000245.4(MET):c.607T>A (p.Ser203Thr)

gnomAD frequency: 0.00053  dbSNP: rs200861145

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081506	SCV000166430	benign	Renal cell carcinoma	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163435	SCV000213982	likely benign	Hereditary cancer-predisposing syndrome	2018-07-10	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	RCV000485340	SCV000572668	likely benign	not specified	2017-08-29	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.
CeGaT Center for Human Genetics Tuebingen	RCV000034533	SCV001155231	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000485340	SCV001478625	benign	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: MET c.607T>A (p.Ser203Thr) results in a conservative amino acid change located in the Sema domain (IPR001627) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 248020 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 400 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.607T>A in individuals affected with Papillary Renal Cell Carcinoma and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant predominantly as benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
Baylor Genetics	RCV001333795	SCV001526479	uncertain significance	Autosomal recessive nonsyndromic hearing loss 97	2018-01-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000163435	SCV002532173	likely benign	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	curation
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034533	SCV000043294	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252075	SCV001427823	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034533	SCV001960113	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000034533	SCV001968696	likely benign	not provided		no assertion criteria provided	clinical testing