Submissions for variant NM_000245.4(MET):c.967A>G (p.Ser323Gly)

gnomAD frequency: 0.00024  dbSNP: rs201467281

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001507142	SCV000166438	benign	Renal cell carcinoma	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563453	SCV000673684	likely benign	Hereditary cancer-predisposing syndrome	2020-10-12	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	RCV000034535	SCV000714695	likely benign	not provided	2019-03-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22703879, 28873162, 16050800, 15735036, 20139696, 26878173, 22363766, 28603720, 25605252, 21904579, 26700204, 22530990)
Mendelics	RCV001507142	SCV000838243	benign	Renal cell carcinoma	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000123136	SCV001327071	likely benign	Papillary renal cell carcinoma type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000599960	SCV001748777	benign	not specified	2021-06-28	criteria provided, single submitter	clinical testing	Variant summary: MET c.967A>G (p.Ser323Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 248794 control chromosomes. The observed variant frequency is approximately 268 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.967A>G 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. Based on the evidence outlined above, the variant was classified as benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034535	SCV002011101	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000563453	SCV002532191	likely benign	Hereditary cancer-predisposing syndrome	2020-08-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000599960	SCV004025157	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034535	SCV000043296	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003944878	SCV004761738	likely benign	MET-related disorder	2020-09-26	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).