NM_000245.4:c.3658G>A

Variant names:

• chr7-116783329-G-A
• rs121913670
• NM_000245.4:c.3658G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000245.4(MET):​c.3658G>A​(p.Val1220Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Pathogenic/Likely 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 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
• PP5: Variant 7-116783329-G-A is Pathogenic according to our data. Variant chr7-116783329-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116783329-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3658G>A	p.Val1220Ile	missense_variant	Exon 19 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3712G>A	p.Val1238Ile	missense_variant	Exon 19 of 21		NP_001120972.1
MET	NM_001324402.2	c.2368G>A	p.Val790Ile	missense_variant	Exon 18 of 20		NP_001311331.1
MET	XM_011516223.2	c.3715G>A	p.Val1239Ile	missense_variant	Exon 20 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3658G>A	p.Val1220Ile	missense_variant	Exon 19 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3712G>A	p.Val1238Ile	missense_variant	Exon 19 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1263G>A		non_coding_transcript_exon_variant	Exon 18 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1263G>A		3_prime_UTR_variant	Exon 18 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727220

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Renal cell carcinoma Pathogenic:1

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1238 of the MET protein (p.Val1238Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with renal cell carcinoma (PMID: 9140397, 32770124, 34882875). It has also been observed to segregate with disease in related individuals. This variant is also known as V1220I. ClinVar contains an entry for this variant (Variation ID: 13883). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MET protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MET function (PMID: 9326629, 19459657). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Papillary renal cell carcinoma type 1 Pathogenic:1

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 03, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1238I pathogenic mutation (also known as c.3712G>A), located in coding exon 18 of the MET gene, results from a G to A substitution at nucleotide position 3712. The valine at codon 1238 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a French patient with papillary renal carcinoma and no known family history of kidney cancer (Schmidt L et al, Oncogene 1999 Apr; 18(14):2343-50). It has also been shown to segregate with disease in a large Spanish family with a clinical history consistent with hereditary papillary renal cell carcinoma (HPRCC) with a likelihood ratio of 348:1 (Schmidt L et al, Nat. Genet. 1997 May; 16(1):68-73; Prat E et al. Cancer Genet Cytogenet, 2006 Jan;164:142-7, Ambry internal calculations). One study examined the functional significance of this alteration by transfecting cells with MET mutant cDNA and found that while cells transfected with V1238I were phenotypically normal, they had moderately enhanced kinase activity toward an exogenous substrate when compared with wild-type MET. Further, cells expressing MET V1238I were shown to be tumorigenic in nude mice (Jeffers M et al, Proc. Natl. Acad. Sci. U.S.A. 1997 Oct; 94(21):11445-50). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.29	N;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.91	N;N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.70
MutPred		0.55		Loss of methylation at K1219 (P = 0.0714);.;
MVP		0.83
MPC		1.7
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.69

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: rs121913670; hg19: chr7-116423383; COSMIC: COSV59262142;