Submissions for variant NM_000245.4(MET):c.3218C>T (p.Pro1073Leu)

gnomAD frequency: 0.00007  dbSNP: rs370529693

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001312227	SCV000166423	uncertain significance	Renal cell carcinoma	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1091 of the MET protein (p.Pro1091Leu). This variant is present in population databases (rs370529693, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MET-related conditions. ClinVar contains an entry for this variant (Variation ID: 135966). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MET protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000164064	SCV000214674	likely benign	Hereditary cancer-predisposing syndrome	2019-03-07	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.
Mendelics	RCV003492548	SCV000838270	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001534185	SCV001751089	uncertain significance	not provided	2024-06-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast and colon cancer (PMID: 29684080, 35264596); This variant is associated with the following publications: (PMID: 35210353, 35264596, 29684080)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228447	SCV002511600	likely benign	not specified	2022-04-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001534185	SCV003808792	uncertain significance	not provided	2019-05-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001534185	SCV005622917	uncertain significance	not provided	2024-07-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031633	SCV005673774	uncertain significance	Osteofibrous dysplasia; Papillary renal cell carcinoma type 1; Hepatocellular carcinoma; Autosomal recessive nonsyndromic hearing loss 97; Arthrogryposis, distal, IIa 11	2024-05-14	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV001534185	SCV005685356	uncertain significance	not provided	2024-07-08	criteria provided, single submitter	clinical testing	A MET c.3218C>T (p.Pro1073Leu) variant was identified at a near heterozygous allelic fraction of 46.6%, a frequency which may be consistent with germline origin. This variant, to our knowledge, has not been reported in the medical literature in individuals with lymphedema or lymphovenous malformation. The MET c.3218C>T (p.Pro1073Leu) variant is observed on 173/1,614,124 alleles in the general population (gnomAD v.4.1.0). This variant has been reported in the ClinVar database as a germline variant of uncertain significance by three submitters as well as a likely benign variant by three submitters (ClinVar ID: 135966). Computational predictors suggest that the variant does not impact MET function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the MET c.3218C>T (p.Pro1073Leu) variant is uncertain at this time.
Myriad Genetics, Inc.	RCV005246658	SCV005896282	likely benign	Papillary renal cell carcinoma type 1	2024-11-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.