7-116763117-T-C

Variant summary

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

The NM_000245.4(MET):​c.2432T>C​(p.Leu811Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MET
NM_000245.4 missense

Scores

2
10
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.25
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
METNM_000245.4 linkuse as main transcriptc.2432T>C p.Leu811Pro missense_variant 11/21 ENST00000397752.8 NP_000236.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
METENST00000397752.8 linkuse as main transcriptc.2432T>C p.Leu811Pro missense_variant 11/211 NM_000245.4 ENSP00000380860 P3P08581-1
METENST00000318493.11 linkuse as main transcriptc.2486T>C p.Leu829Pro missense_variant 11/211 ENSP00000317272 A2P08581-2
METENST00000436117.3 linkuse as main transcriptc.*37T>C 3_prime_UTR_variant, NMD_transcript_variant 10/201 ENSP00000410980 P08581-3
METENST00000422097.2 linkuse as main transcriptc.2432T>C p.Leu811Pro missense_variant 11/123 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
LINK: link

Submissions by phenotype

Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 08, 2021This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 829 of the MET protein (p.Leu829Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MET-related conditions. ClinVar contains an entry for this variant (Variation ID: 659224). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 08, 2023The p.L829P variant (also known as c.2486T>C), located in coding exon 10 of the MET gene, results from a T to C substitution at nucleotide position 2486. The leucine at codon 829 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.27
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
T;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.83
T;T;T
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.61
D;D;D
MetaSVM
Uncertain
0.049
D
MutationAssessor
Uncertain
2.2
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
1.1
N;N;N
REVEL
Uncertain
0.43
Sift
Benign
0.12
T;T;D
Sift4G
Benign
0.22
T;T;D
Polyphen
1.0
D;D;.
Vest4
0.47
MutPred
0.47
Gain of disorder (P = 0.0089);.;.;
MVP
0.82
MPC
1.1
ClinPred
0.92
D
GERP RS
5.8
Varity_R
0.30
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs1554396554; hg19: chr7-116403171; API