7-116771936-C-T

Position:

• chr7-116771936-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000245.4(MET):​c.2975C>T​(p.Thr992Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,613,864 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0088 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (117 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:22 O:1
• Conservation: PhyloP100: 7.36

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007516116).
• BP6: Variant 7-116771936-C-T is Benign according to our data. Variant chr7-116771936-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41624.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Benign=15}. Variant chr7-116771936-C-T is described in Lovd as [Likely_benign]. Variant chr7-116771936-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00881 (1341/152268) while in subpopulation NFE AF= 0.0132 (895/68020). AF 95% confidence interval is 0.0124. There are 8 homozygotes in gnomad4. There are 654 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.2975C>T	p.Thr992Ile	missense_variant	14/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3029C>T	p.Thr1010Ile	missense_variant	14/21		NP_001120972.1
MET	NM_001324402.2	c.1685C>T	p.Thr562Ile	missense_variant	13/20		NP_001311331.1
MET	XM_011516223.2	c.3032C>T	p.Thr1011Ile	missense_variant	15/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.2975C>T	p.Thr992Ile	missense_variant	14/21	1	NM_000245.4	ENSP00000380860.3

Frequencies

GnomAD3 genomes AF: 0.00881 AC: 1341 AN: 152150 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00789 AC: 1962 AN: 248630 Hom.: 11 AF XY: 0.00812 AC XY: 1095 AN XY: 134836

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.0110 AC: 16025 AN: 1461596 Hom.: 117 Cov.: 32 AF XY: 0.0109 AC XY: 7920 AN XY: 727098

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00804

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00176

Gnomad4 FIN exome AF: 0.0197

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.00911

GnomAD4 genome AF: 0.00881 AC: 1341 AN: 152268 Hom.: 8 Cov.: 32 AF XY: 0.00878 AC XY: 654 AN XY: 74446

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0109 Hom.: 18

Bravo AF: 0.00690

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00107 AC: 4

ESP6500EA AF: 0.0125 AC: 102

ExAC AF: 0.00790 AC: 954

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:22 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2016	Variant summary: The c.3029C>T (p.Thr1010Ile) in MET gene is a missense change that involves a conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant falls into c-MET JM domain that regulates cytoskeletal functions: adhesion, motility, and migration and Mutation in this domain were shown to enhance lung cancer tumorigenicity in vitro. The variant is present in the control population dataset of ExAC and published general population data at an overall frequency 0.008 (962/1217700 chrs tested) including 6 homozygotes. It has particularly higher frequency in African subpopulation with an allele frequency of 2% (134/6576 chromosomes). These frequencies exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000015). The variant has been reported in healthy individuals and metastatic breast cancer, lung cancer and colorectal cancer patients (Liu_2015, Agrawal_2015). However, it has not been associated with increased risk for developing breast cancer in large genome wide association studies and previous laboratory studies have reported conflicting functional effects for the T1010I variant in NIH3T3 fibroblast and murine myeloid BA/F3 cell line models as discussed by Liu et al (Agrawal_2015). The variant is reported as Benign/VUS/Functional Polymorphism by a multiple reputable databases/clinical laboratories and published reports. Taken together, the variant was classified as Benign. -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MET: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 18, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 18, 2019	- -

not specified Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 29, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 20, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Papillary renal cell carcinoma type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 17, 2021	The MET c.3029C>T (p.Thr1010Ile) missense change is present at a maximum non-founder subpopulation frequency of 1.2% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-116411990-C-T?dataset=gnomad_r2_1). This population frequency is higher than expected for a pathogenic variant in MET causing predisposition to hereditary papillary renal cell carcinoma (BS1). This variant has also been reported as homozygous 13 times in the gnomAD v2.1.1 database which suggests that this is a benign polymorphism (BS2). In silico tools are not in agreement about the effect on the gene or protein function, and functional studies have reported conflicting effects in cell line models (PMIDs: 14559814, 25605252). This variant has been identified in individuals with colorectal cancer (PMID: 21970370), metastatic breast cancer (PMID: 25605252), and those without a personal or family history of hereditary papillary renal cell carcinoma (internal data). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria: BS1, BS2. -

Classic Hodgkin lymphoma Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Pathology Department, Puerta del Mar University Hospital

Oct 01, 2021

- -

Congenital diaphragmatic hernia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Mar 03, 2015

It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. -

MET-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Renal cell carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0075	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		1.0	D;D
Vest4		0.63
MVP		0.61
MPC		0.77
ClinPred		0.023	T
GERP RS		5.7
Varity_R		0.22
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs56391007; hg19: chr7-116411990; COSMIC: COSV59256560; COSMIC: COSV59256560;