7-116757511-C-T

Position:

• chr7-116757511-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000245.4(MET):​c.1937C>T​(p.Thr646Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.254

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10052428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.1937C>T	p.Thr646Ile	missense_variant	7/21	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.1937C>T	p.Thr646Ile	missense_variant	7/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.1937C>T	p.Thr646Ile	missense_variant	7/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.1937C>T	p.Thr646Ile	missense_variant, NMD_transcript_variant	7/20	1		ENSP00000410980
MET	ENST00000422097.2	c.1937C>T	p.Thr646Ile	missense_variant	7/12	3		ENSP00000398776

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 30, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt MET protein function. ClinVar contains an entry for this variant (Variation ID: 1513797). This variant has not been reported in the literature in individuals affected with MET-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 646 of the MET protein (p.Thr646Ile). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2024

The p.T646I variant (also known as c.1937C>T), located in coding exon 6 of the MET gene, results from a C to T substitution at nucleotide position 1937. The threonine at codon 646 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	3.4
DANN	Benign	0.94
DEOGEN2	Uncertain	0.56	D;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.11
Sift	Benign	0.081	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.076	B;B;.
Vest4		0.12
MutPred		0.52		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.44
MPC		0.29
ClinPred		0.087	T
GERP RS		3.3
Varity_R		0.17
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116397565;