7-116783420-T-C

Position:

• chr7-116783420-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000245.4(MET):​c.3749T>C​(p.Met1250Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1250I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.02

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 12 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity MET_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) 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 chr7-116783421-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 7-116783420-T-C is Pathogenic according to our data. Variant chr7-116783420-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-116783420-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3749T>C	p.Met1250Thr	missense_variant	19/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3803T>C	p.Met1268Thr	missense_variant	19/21		NP_001120972.1
MET	NM_001324402.2	c.2459T>C	p.Met820Thr	missense_variant	18/20		NP_001311331.1
MET	XM_011516223.2	c.3806T>C	p.Met1269Thr	missense_variant	20/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3749T>C	p.Met1250Thr	missense_variant	19/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.3803T>C	p.Met1268Thr	missense_variant	19/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*1354T>C		3_prime_UTR_variant, NMD_transcript_variant	18/20	1		ENSP00000410980

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

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.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The p.M1268T variant (also known as c.3803T>C), located in coding exon 18 of the MET gene, results from a T to C substitution at nucleotide position 3803. The methionine at codon 1268 is replaced by threonine, an amino acid with similar properties. This variant has been reported in individuals with papillary renal cell carcinoma (Lubensky IA et al. Am J Pathol, 1999 Aug;155:517-26) including a patient with bilateral disease (Ambry internal data). This variant has shown constitutive kinase activity in multiple functional studies and renders MET more sensitive to MET inhibitors (Jeffers M et al. Proc Natl Acad Sci U S A, 1997 Oct;94:11445-50; Bardelli A et al. Proc Natl Acad Sci U S A, 1998 Nov;95:14379-83; Medová M et al. Int J Cancer, 2012 Feb;130:728-34). Cells expressing M1268T showed its accumulation in intracellular vesicles at higher levels than wild type MET; this was associated with increasing tumorgenicity (Joffre C et al. Nat Cell Biol, 2011 Jun;13:827-37). Based on internal structural analysis, M1268T disrupts a key position in the kinase P+1 loop which plays a role in substrate recognition (Xu W et al. Nature, 1997 Feb;385:595-602; Schmidt L et al. Oncogene, 1999 Apr;18:2343-50; Miller M et al. Proteins, 2001 Jul;44:32-43; Yuan ZL et al. Mol Cell Biol, 2004 Nov;24:9390-400; Yuan H et al. Eur J Med Chem, 2018 Jan;143:491-502). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Renal carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.84		Loss of sheet (P = 0.1158);.;
MVP		0.86
MPC		2.0
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

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: rs121913245; hg19: chr7-116423474; COSMIC: COSV59255872;