rs121913246

Positions:

• chr7-116783360-A-G
• chr7-116783360-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000245.4(MET):​c.3689A>G​(p.Tyr1230Cys) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1230D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.01

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a turn (size 3) in uniprot entity MET_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873
• PP5: Variant 7-116783360-A-G is Pathogenic according to our data. Variant chr7-116783360-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13885.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr7-116783360-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3689A>G	p.Tyr1230Cys	missense_variant	19/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3743A>G	p.Tyr1248Cys	missense_variant	19/21		NP_001120972.1
MET	NM_001324402.2	c.2399A>G	p.Tyr800Cys	missense_variant	18/20		NP_001311331.1
MET	XM_011516223.2	c.3746A>G	p.Tyr1249Cys	missense_variant	20/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3689A>G	p.Tyr1230Cys	missense_variant	19/21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3743A>G	p.Tyr1248Cys	missense_variant	19/21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1294A>G		non_coding_transcript_exon_variant	18/20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1294A>G		3_prime_UTR_variant	18/20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Papillary renal cell carcinoma type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9140397, 34882875]. Functional studies indicate this variant impacts protein function [PMID: 9326629, 9826708, 10498872]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1997	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2021

The p.Y1248C variant (also known as c.3743A>G), located in coding exon 18 of the MET gene, results from an A to G substitution at nucleotide position 3743. The tyrosine at codon 1248 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant is reported in an individual with bilateral papillary renal cell carcinoma and gastric cancer (Schmidt L et al. Nat Genet, 1997 May;16:68-73). Functional studies indicate that the p.Y1248C alteration increases tyrosine kinase activity and confers cell transformation properties (Jeffers M et al. Proc Natl Acad Sci U S A, 1997 Oct;94:11445-50). Based on structural analysis, this variant is located in the tyrosine kinase domain and is mildly destabilizing to the local structure (Yuan H et al. Eur J Med Chem, 2018 Jan;143:491-502; Ambry internal data). This amino acid position is well conserved in available vertebrate species.This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2021

This variant has been observed in an individual with bilateral papillary renal carcinoma, stomach cancer, and rectal cancer (PMID: 9140397). ClinVar contains an entry for this variant (Variation ID: 13885). 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. Experimental studies have shown that this variant affects MET protein function (PMID: 9826708). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 1248 of the MET protein (p.Tyr1248Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.68		Loss of phosphorylation at Y1230 (P = 0.0464);.;
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.93

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: rs121913246; hg19: chr7-116423414; COSMIC: COSV59257466;