NM_000245.4:c.2908C>T

Variant names:

• chr7-116771869-C-T
• rs34589476
• NM_000245.4:c.2908C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000245.4(MET):​c.2908C>T​(p.Arg970Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,613,774 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R970H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (17 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:23 O:1
• Conservation: PhyloP100: 3.57
• Publications: 72 publications found

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 Gene-Disease associations (from GenCC):

• hereditary papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen
• autosomal recessive nonsyndromic hearing loss 97

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteofibrous dysplasia

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arthrogryposis, distal, IIa 11

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009256214).
• BP6: Variant 7-116771869-C-T is Benign according to our data. Variant chr7-116771869-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41623.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00312 (475/152220) while in subpopulation NFE AF = 0.00532 (362/68012). AF 95% confidence interval is 0.00487. There are 3 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.2908C>T	p.Arg970Cys	missense	Exon 14 of 21	NP_000236.2
	MET	NM_001127500.3		c.2962C>T	p.Arg988Cys	missense	Exon 14 of 21	NP_001120972.1
	MET	NM_001324402.2		c.1618C>T	p.Arg540Cys	missense	Exon 13 of 20	NP_001311331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.2908C>T	p.Arg970Cys	missense	Exon 14 of 21	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.2962C>T	p.Arg988Cys	missense	Exon 14 of 21	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.*513C>T		non_coding_transcript_exon	Exon 13 of 20	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152102 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00288 AC: 717 AN: 248552 AF XY: 0.00297

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.000929

Gnomad NFE exome AF: 0.00520

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.00473 AC: 6915 AN: 1461554 Hom.: 17 Cov.: 32 AF XY: 0.00453 AC XY: 3291 AN XY: 727066

African (AFR) AF: 0.000986 AC: 33 AN: 33460

American (AMR) AF: 0.00123 AC: 55 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26126

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39666

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86248

European-Finnish (FIN) AF: 0.00124 AC: 66 AN: 53390

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00583 AC: 6478 AN: 1111810

Other (OTH) AF: 0.00283 AC: 171 AN: 60378

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152220 Hom.: 3 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74442

African (AFR) AF: 0.000867 AC: 36 AN: 41546

American (AMR) AF: 0.00157 AC: 24 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00532 AC: 362 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00459 Hom.: 8

Bravo AF: 0.00328

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000798 AC: 3

ESP6500EA AF: 0.00475 AC: 39

ExAC AF: 0.00284 AC: 343

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:23 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:9

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

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

Jan 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 18, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 06, 2023

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

BA1 based on allele frequency in NFE of 0.0050422 in gnomAD. PMID:20670955 variant lacks transforming ability.

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MET: BS2

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17322284, 17053076, 20670955, 25314153, 20368753, 23401458, 22128285, 25231402, 16734685, 25992381, 27626278, 28085233, 27636102, no PMID, 29970518, 14559814, 24728327, 23449277, 16189274, 15592501, 21847116, 15735036, 19723643, 26097886, 18564920, 22703879, 17404109, 23640142, 20370683, 20139696, 19037978, 18340114, 19318576, 17288874, 19861919, 17483355, 23662036, 19333071, 18709663, 20462834, 22838389, 20489150, 19393836, 21918175, 22530990, 25868855, 24327519, 24105670, 25416047, 24929890, 22973954, 26574927, 27153395, 28648934, 28116210, 27741505, 27899992, 28247034, 27013592, 28061464, 26934580, 27376238, 28603720, 28740441, 27923392, 28476232, 28619094, 31004003)

not specified Uncertain:1 Benign:4 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

May 04, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

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 31, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with cancers, and variant has been identified in large B-cell lymphoma, but also pretty high frequency in ExAC with 1 homozygote, reported in apparently healthy individuals, and there are conflicting reports about functional impact (most recent functional study says no impact)

Papillary renal cell carcinoma type 1 Benign:5

Jul 02, 2018

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 21, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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.

Hereditary cancer-predisposing syndrome Benign:2

Oct 23, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Sep 27, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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.

MET-related disorder Benign:1

Nov 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: 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).

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

Papillary renal cell carcinoma type 1;C2239176:Hepatocellular carcinoma;C4084709:Autosomal recessive nonsyndromic hearing loss 97;C4085248:Osteofibrous dysplasia;C5774205:Arthrogryposis, distal, IIa 11 Benign:1

Jun 20, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.17
Sift	Uncertain	0.027	D
Sift4G	Benign	0.18	T
Polyphen		0.026	B
Vest4		0.37
MVP		0.66
MPC		0.35
ClinPred		0.19	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.61
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34589476; hg19: chr7-116411923; COSMIC: COSV59257461; COSMIC: COSV59257461;