7-116771936-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000245.4(MET):c.2975C>T(p.Thr992Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,613,864 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0088 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 117 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:23O:1

Conservation

PhyloP100: 7.36

Variant links:

Genes affected

MET (HGNC:7029): (MET proto-oncogene, receptor tyrosine kinase) This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016]

MET links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007516116).

BP6

Variant 7-116771936-C-T is Benign according to our data. Variant chr7-116771936-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41624.We mark this variant Likely_benign, oryginal submissions are: {Benign=15, Uncertain_significance=3, not_provided=1}. Variant chr7-116771936-C-T is described in Lovd as [Likely_benign]. Variant chr7-116771936-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00881 (1341/152268) while in subpopulation NFE AF= 0.0132 (895/68020). AF 95% confidence interval is 0.0124. There are 8 homozygotes in gnomad4. There are 654 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4 link	c.2975C>T	p.Thr992Ile	missense_variant	Exon 14 of 21	ENST00000397752.8	NP_000236.2	P08581-1A0A024R759
MET	NM_001127500.3 link	c.3029C>T	p.Thr1010Ile	missense_variant	Exon 14 of 21		NP_001120972.1	P08581-2A0A024R728
MET	NM_001324402.2 link	c.1685C>T	p.Thr562Ile	missense_variant	Exon 13 of 20		NP_001311331.1	B4DLF5
MET	XM_011516223.2 link	c.3032C>T	p.Thr1011Ile	missense_variant	Exon 15 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8 link	c.2975C>T	p.Thr992Ile	missense_variant	Exon 14 of 21	1	NM_000245.4	ENSP00000380860.3		P08581-1

Frequencies

GnomAD3 genomes

AF:

0.00881

AC:

1341

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.00341

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0132

Gnomad OTH

AF:

0.00907

GnomAD3 exomes

AF:

0.00789

AC:

1962

AN:

248630

Hom.:

AF XY:

0.00812

AC XY:

1095

AN XY:

134836

show subpopulations

Gnomad AFR exome

AF:

0.00187

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.00796

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.0195

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00945

GnomAD4 exome

AF:

0.0110

AC:

16025

AN:

1461596

Hom.:

117

Cov.:

AF XY:

0.0109

AC XY:

7920

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.00170

Gnomad4 ASJ exome

AF:

0.00804

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00176

Gnomad4 FIN exome

AF:

0.0197

Gnomad4 NFE exome

AF:

0.0125

Gnomad4 OTH exome

AF:

0.00911

GnomAD4 genome

AF:

0.00881

AC:

1341

AN:

152268

Hom.:

Cov.:

AF XY:

0.00878

AC XY:

654

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.0216

Gnomad4 NFE

AF:

0.0132

Gnomad4 OTH

AF:

0.00898

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00690

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00107

AC:

ESP6500EA

AF:

0.0125

AC:

102

ExAC

AF:

0.00790

AC:

954

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:23Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:8

Jul 18, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 18, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.3029C>T (p.Thr1010Ile) in MET gene is a missense change that involves a conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant falls into c-MET JM domain that regulates cytoskeletal functions: adhesion, motility, and migration and Mutation in this domain were shown to enhance lung cancer tumorigenicity in vitro. The variant is present in the control population dataset of ExAC and published general population data at an overall frequency 0.008 (962/1217700 chrs tested) including 6 homozygotes. It has particularly higher frequency in African subpopulation with an allele frequency of 2% (134/6576 chromosomes). These frequencies exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000015). The variant has been reported in healthy individuals and metastatic breast cancer, lung cancer and colorectal cancer patients (Liu_2015, Agrawal_2015). However, it has not been associated with increased risk for developing breast cancer in large genome wide association studies and previous laboratory studies have reported conflicting functional effects for the T1010I variant in NIH3T3 fibroblast and murine myeloid BA/F3 cell line models as discussed by Liu et al (Agrawal_2015). The variant is reported as Benign/VUS/Functional Polymorphism by a multiple reputable databases/clinical laboratories and published reports. Taken together, the variant was classified as Benign. -

Jul 18, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MET: BS1, BS2 -

not specified

Benign:7Other:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Papillary renal cell carcinoma type 1

Benign:4

Mar 17, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MET c.3029C>T (p.Thr1010Ile) missense change is present at a maximum non-founder subpopulation frequency of 1.2% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-116411990-C-T?dataset=gnomad_r2_1). This population frequency is higher than expected for a pathogenic variant in MET causing predisposition to hereditary papillary renal cell carcinoma (BS1). This variant has also been reported as homozygous 13 times in the gnomAD v2.1.1 database which suggests that this is a benign polymorphism (BS2). In silico tools are not in agreement about the effect on the gene or protein function, and functional studies have reported conflicting effects in cell line models (PMIDs: 14559814, 25605252). This variant has been identified in individuals with colorectal cancer (PMID: 21970370), metastatic breast cancer (PMID: 25605252), and those without a personal or family history of hereditary papillary renal cell carcinoma (internal data). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria: BS1, BS2. -

Jul 02, 2018

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Jul 20, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 01, 2015

Vantari Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Classic Hodgkin lymphoma

Uncertain:1

Oct 01, 2021

Pathology Department, Puerta del Mar University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Congenital diaphragmatic hernia

Uncertain:1

Mar 03, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. -

MET-related disorder

Benign:1

Jun 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Renal cell carcinoma

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0075

T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.031

D;D

Polyphen

1.0

D;D

Vest4

0.63

MVP

0.61

MPC

0.77

ClinPred

0.023

GERP RS

5.7

Varity_R

0.22

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over