chr7-116778827-T-C

Position:

• chr7-116778827-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000397752.8(MET):​c.3392T>C​(p.Met1131Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET ENST00000397752.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts 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 16 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity MET_HUMAN there are 42 pathogenic changes around while only 14 benign (75%) in ENST00000397752.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 7-116778827-T-C is Pathogenic according to our data. Variant chr7-116778827-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116778827-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.3392T>C	p.Met1131Thr	missense_variant	17/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3446T>C	p.Met1149Thr	missense_variant	17/21		NP_001120972.1
MET	NM_001324402.2	c.2102T>C	p.Met701Thr	missense_variant	16/20		NP_001311331.1
MET	XM_011516223.2	c.3449T>C	p.Met1150Thr	missense_variant	18/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3392T>C	p.Met1131Thr	missense_variant	17/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.3446T>C	p.Met1149Thr	missense_variant	17/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*997T>C		3_prime_UTR_variant, NMD_transcript_variant	16/20	1		ENSP00000410980

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cell carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2018

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect MET protein function (PMID: 9326629). This variant has been observed to segregate with papillary renal cell carcinoma in two families (PMID: 9140397). ClinVar contains an entry for this variant (Variation ID: 13881). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 1149 of the MET protein (p.Met1149Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. -

Papillary renal cell carcinoma type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1997

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2016

The p.M1149T pathogenic mutation (also known as c.3446T>C), located in coding exon 16 of the MET gene, results from a T to C substitution at nucleotide position 3446. The methionine at codon 1149 is replaced by threonine, an amino acid with similar properties. This alteration has been previously in two families with hereditary papillary renal cell carcinoma, and was shown to segregate with disease (Schmidt L et al. Nat. Genet., 1997 May;16:68-73). Based on structural analysis, this variant is located in the tyrosine kinase domain and is anticipated to perturb normal protein function (Miller M et al. Proteins, 2001 Jul;44:32-43). Functional assays demonstrated that this is a weakly activating mutation resulting in increased phosphorylation (Jeffers M et al. Proc. Natl. Acad. Sci. U.S.A., 1997 Oct;94:11445-50; Schmidt L et al. Oncogene, 1999 Apr;18:2343-50). 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	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.89		Gain of methylation at K1132 (P = 0.0294);.;
MVP		0.96
MPC		2.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.91

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: rs121913668; hg19: chr7-116418881; COSMIC: COSV59261962; COSMIC: COSV59261962;