Submissions for variant NM_000245.4(MET):c.948A>G (p.Ile316Met)

gnomAD frequency: 0.00641  dbSNP: rs35225896

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079499	SCV000111381	benign	not specified	2012-12-06	criteria provided, single submitter	clinical testing
Invitae	RCV001507202	SCV000153823	benign	Renal cell carcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163441	SCV000213988	benign	Hereditary cancer-predisposing syndrome	2014-12-12	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.
PreventionGenetics, part of Exact Sciences	RCV000079499	SCV000306721	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119111	SCV000466431	benign	Papillary renal cell carcinoma type 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	RCV000034534	SCV000524818	benign	not provided	2018-05-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21904579, 24728327, 31801140)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034534	SCV000604221	benign	not provided	2022-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000079499	SCV001774635	benign	not specified	2021-08-01	criteria provided, single submitter	clinical testing	Variant summary: MET c.948A>G (p.Ile316Met) results in a conservative amino acid change located in the Sema domain (IPR001627) 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 0.0016 in 248850 control chromosomes. The observed variant frequency is approximately 1085 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.948A>G 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. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000163441	SCV002532188	benign	Hereditary cancer-predisposing syndrome	2021-04-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000079499	SCV002550775	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490458	SCV002804263	likely benign	Osteofibrous dysplasia; Papillary renal cell carcinoma type 1; Hepatocellular carcinoma; Autosomal recessive nonsyndromic hearing loss 97	2022-05-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034534	SCV004158932	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MET: BS1, BS2
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034534	SCV000043295	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000079499	SCV000085519	not provided	not specified	2013-09-19	no assertion provided	reference population