7-116771932-C-T

Position:

• chr7-116771932-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_000245.4(MET):​c.2971C>T​(p.Pro991Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P991L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.65

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33359808).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000013 (19/1461624) while in subpopulation EAS AF= 0.000479 (19/39684). AF 95% confidence interval is 0.000313. There are 0 homozygotes in gnomad4_exome. There are 11 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.2971C>T	p.Pro991Ser	missense_variant	14/21	ENST00000397752.8
MET	NM_001127500.3	c.3025C>T	p.Pro1009Ser	missense_variant	14/21
MET	NM_001324402.2	c.1681C>T	p.Pro561Ser	missense_variant	13/20
MET	XM_011516223.2	c.3028C>T	p.Pro1010Ser	missense_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.2971C>T	p.Pro991Ser	missense_variant	14/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.3025C>T	p.Pro1009Ser	missense_variant	14/21	1		A2
MET	ENST00000436117.3	c.*576C>T		3_prime_UTR_variant, NMD_transcript_variant	13/20	1
MET	ENST00000454623.1	c.283+278C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000282 AC: 7 AN: 248608 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000390

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461624 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000479

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.: 32

Alfa AF: 0.0000333 Hom.: 0

ExAC AF: 0.0000331 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Osteofibrous dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 25, 2021

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2021

In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect: increased and persistent tyrosine phosphorylation, colony formation in soft agar, and tumorgeneis in athymic mice (Lee 2000); This variant is associated with the following publications: (PMID: 11042681) -

Papillary renal cell carcinoma type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2022

The p.P1009S variant (also known as c.3025C>T), located in coding exon 13 of the MET gene, results from a C to T substitution at nucleotide position 3025. The proline at codon 1009 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a patient with primary gastric cancer (Lee JH et al. Oncogene, 2000 Oct;19:4947-53). Lee et al. (2000) also examined the impact of this alteration in when expressed in a mouse embryonic fibroblast cell line and found it results in increased tyrosine phosphorylation compared to wild-type, as well as highly tumorigenic colony formation in soft agar, leading authors to conclude that it could contribute to tumorigenesis of gastric cancer. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Renal cell carcinoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.048	D;D
Sift4G	Benign	0.071	T;T
Polyphen		1.0	D;D
Vest4		0.53
MutPred		0.30		Gain of phosphorylation at P991 (P = 0.0454);.;
MVP		0.61
MPC		0.55
ClinPred		0.46	T
GERP RS		5.7
Varity_R		0.20
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs768678989; hg19: chr7-116411986; COSMIC: COSV59266319; COSMIC: COSV59266319;