chr7-116777403-G-A

Position:

• chr7-116777403-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000245.4(MET):​c.3274G>A​(p.Val1092Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1092L) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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 chr7-116777403-G-T is described in Lovd as [Pathogenic].
• PP5: Variant 7-116777403-G-A is Pathogenic according to our data. Variant chr7-116777403-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 186141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116777403-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3274G>A	p.Val1092Ile	missense_variant	16/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3328G>A	p.Val1110Ile	missense_variant	16/21		NP_001120972.1
MET	NM_001324402.2	c.1984G>A	p.Val662Ile	missense_variant	15/20		NP_001311331.1
MET	XM_011516223.2	c.3331G>A	p.Val1111Ile	missense_variant	17/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3274G>A	p.Val1092Ile	missense_variant	16/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.3328G>A	p.Val1110Ile	missense_variant	16/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*879G>A		3_prime_UTR_variant, NMD_transcript_variant	15/20	1		ENSP00000410980

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

Carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Renal cell carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1110 of the MET protein (p.Val1110Ile). This variant is present in population databases (rs786202724, gnomAD 0.007%). This missense change has been observed in individual(s) with hereditary papillary renal cell carcinoma (PMID: 10417759, 10433944, 15371818, 22717761, 24658158). It has also been observed to segregate with disease in related individuals. This variant is also known as V1092I, c.3522G>A. ClinVar contains an entry for this variant (Variation ID: 186141). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MET protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MET function (PMID: 10417759). For these reasons, this variant has been classified as Pathogenic. -

Papillary renal cell carcinoma type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2014

The p.V1110I pathogenic mutation (also known as c.3328G>A), located in coding exon 15 of the MET gene, results from a G to A substitution at nucleotide position 3328. The valine at codon 1110 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been previously described in numerous individuals with Hereditary Papillary Renal Carcinoma (HPRC) diagnosed with multifocal or bilateral papillary renal cell carcinoma and has been found to segregate with disease in several families (Olivero M, Int. J. Cancer 1999 Aug; 82(5):640-3; Schmidt LS, J. Urol. 2004 Oct; 172(4 Pt 1):1256-61; Lubensky IA, Am. J. Pathol. 1999 Aug; 155(2):517-26) . Functional studies indicate that the V1110I mutant increases tyrosine kinase activity and confers cell transformation properties (Olivero M, Int. J. Cancer 1999 Aug; 82(5):640-3). The MET V1110 residue is located in the ATP-binding site of the tyrosine kinase domain and mutations are believed to affect contact with other residues preventing self-inhibition of the activation loop (Danilkovitch-Miagkova A, J. Clin. Invest. 2002 Apr; 109(7):863-7). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.V1110I is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	0.019	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.88	N;N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.81
MutPred		0.54		Gain of catalytic residue at L1097 (P = 0.0675);.;
MVP		0.88
MPC		0.79
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.63

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

Other links and lift over

dbSNP: rs786202724; hg19: chr7-116417457; COSMIC: COSV59257346; COSMIC: COSV59257346;