chr7-116777410-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000245.4(MET):c.3281A>G(p.His1094Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1094L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.32

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a strand (size 8) in uniprot entity MET_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000245.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

PP5

Variant 7-116777410-A-G is Pathogenic according to our data. Variant chr7-116777410-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116777410-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4 link	c.3281A>G	p.His1094Arg	missense_variant	Exon 16 of 21	ENST00000397752.8	NP_000236.2	P08581-1A0A024R759
MET	NM_001127500.3 link	c.3335A>G	p.His1112Arg	missense_variant	Exon 16 of 21		NP_001120972.1	P08581-2A0A024R728
MET	NM_001324402.2 link	c.1991A>G	p.His664Arg	missense_variant	Exon 15 of 20		NP_001311331.1	B4DLF5
MET	XM_011516223.2 link	c.3338A>G	p.His1113Arg	missense_variant	Exon 17 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MET	ENST00000397752.8 link	c.3281A>G	p.His1094Arg	missense_variant	Exon 16 of 21	1	NM_000245.4	ENSP00000380860.3	P08581-1
MET	ENST00000318493.11 link	c.3335A>G	p.His1112Arg	missense_variant	Exon 16 of 21	1		ENSP00000317272.6	P08581-2
MET	ENST00000436117.3 link	n.*886A>G		non_coding_transcript_exon_variant	Exon 15 of 20	1		ENSP00000410980.2	P08581-3
MET	ENST00000436117.3 link	n.*886A>G		3_prime_UTR_variant	Exon 15 of 20	1		ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249346

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461558

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: results in malignant transformation of transfected cells and causes tumor development in a mouse model (PMID: 9563489); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10433944, 26536169, 12460923, 9563489, 9731534, 9715275, 27047956, 28603720, 28498286, 15122209, 28164088, 29625052, 32770124, 36451132, 38496821) -

MET-related disorder

Pathogenic:1

May 25, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MET c.3335A>G variant is predicted to result in the amino acid substitution p.His1112Arg. This variant has been reported to segregate with papillary renal carcinoma in two extended North American families (Schmidt et al. 1998. PubMed ID: 9563489; Zhuang et al. 1998. PubMed ID: 9731534). Analysis of 23 family members indicated that this variant is associated with late-onset malignancy of low penetrance (Schmidt et al. 1998. PubMed ID: 9563489). This variant has also been reported in additional individuals with papillary renal carcinoma (Table 2, Denize et al. 2020. PubMed ID: 32770124). This variant is reported in 3 of ~249,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/7-116417464-A-G). It is interpreted as likely pathogenic and pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/13887/). This variant is interpreted as pathogenic. -

Renal cell carcinoma

Pathogenic:1

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1112 of the MET protein (p.His1112Arg). This variant is present in population databases (rs121913243, gnomAD 0.003%). This missense change has been observed in individual(s) with papillary renal cell carcinoma (PMID: 9563489, 10327054, 23213094). It has also been observed to segregate with disease in related individuals. This variant is also known as H1094R. ClinVar contains an entry for this variant (Variation ID: 13887). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MET protein function. Experimental studies have shown that this missense change affects MET function (PMID: 9563489). For these reasons, this variant has been classified as Pathogenic. -

Papillary renal cell carcinoma type 1

Pathogenic:1

Sep 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Pathogenic:1

Nov 26, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Nov 12, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H1112R pathogenic mutation (also known as c.3335A>G), located in coding exon 15 of the MET gene, results from an A to G substitution at nucleotide position 3335. The histidine at codon 1112 is replaced by arginine, an amino acid with highly similar properties. This mutation has been detected in two North American hereditary papillary renal carcinoma (HPRC) families and shown to segregate with disease in both families. This mutation was also detected in an unrelated German patient with HPRC in the same study. In a transformation assay performed by the authors, the p.H1112R alteration was shown to produce tumors at the site of inoculation in 10 of 10 nude mice in 2-3 weeks whereas wildtype inoculation did not form tumors (Schmidt L et al. Cancer Res., 1998 Apr;58:1719-22). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-0.58

MutationAssessor

Benign

-1.2

N;.

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;P

Vest4

0.94

MutPred

0.78

Gain of methylation at H1094 (P = 0.0601);.;

MVP

0.87

MPC

0.99

ClinPred

0.99

GERP RS

5.3

Varity_R

0.94

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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