VCV000134649.30 - ClinVar

NM_000245.4(MET):c.71G>A (p.Gly24Glu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(1); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000245.4(MET):c.71G>A (p.Gly24Glu)

Variation ID: 134649 Accession: VCV000134649.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 116699155 (GRCh38) [ NCBI UCSC ] 7: 116339209 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 9, 2014	Oct 8, 2024	Aug 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000245.4:c.71G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000236.2:p.Gly24Glu	missense
NM_001127500.2:c.71G>A
NM_001127500.3:c.71G>A	NP_001120972.1:p.Gly24Glu	missense
NM_001324401.3:c.71G>A	NP_001311330.1:p.Gly24Glu	missense
NM_001324402.2:c.-91+26578G>A		intron variant
NC_000007.14:g.116699155G>A
NC_000007.13:g.116339209G>A
NG_008996.1:g.31751G>A
LRG_662:g.31751G>A
LRG_662t1:c.71G>A

... more HGVS ... less HGVS

Protein change

G24E

Other names

Canonical SPDI

NC_000007.14:116699154:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00014

1000 Genomes Project 30x 0.00016

Exome Aggregation Consortium (ExAC) 0.00017

1000 Genomes Project 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00033

The Genome Aggregation Database (gnomAD) 0.00055

Trans-Omics for Precision Medicine (TOPMed) 0.00062

Links

ClinGen: CA160439 dbSNP: rs180985111 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MET		No evidence available	No evidence available	GRCh38 GRCh37	3775	3826

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Apr 29, 2024	RCV000121347.5
Lymphedema	Likely benign (1)	no assertion criteria provided	Jun 1, 2014	RCV000148614.4
Papillary renal cell carcinoma type 1	Likely benign (1)	criteria provided, single submitter	Jul 2, 2018	RCV000167873.10
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Nov 1, 2021	RCV000210818.10
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 7, 2024	RCV001560219.8
Renal cell carcinoma	Likely benign (1)	criteria provided, single submitter	Jan 29, 2024	RCV001450079.8
MET-related disorder	Likely benign (1)	no assertion criteria provided	Aug 1, 2022	RCV003965017.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Dec 07, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Vantari Genetics Accession: SCV000267041.1 First in ClinVar: Apr 14, 2016 Last updated: Apr 14, 2016
Uncertain significance (Nov 01, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532182.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The MET c.71G>A (p.Gly24Glu) variant has been reported in heterozygosity in at least one individual with renal cell carcinoma (PMID: 24339735). It was also identified … (more) The MET c.71G>A (p.Gly24Glu) variant has been reported in heterozygosity in at least one individual with renal cell carcinoma (PMID: 24339735). It was also identified in at least one individual with lymphedema (PMID: 30530636), and has also been reported in healthy individuals (PMID: 24728327). This variant was observed in 44/24192 chromosomes in the African/African American population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 134649). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. There is no indication that this variant causes disease, but the evidence is insufficient currently to prove that conclusively. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (3) PubMed: 24339735‚ 30530636‚ 24728327
Likely benign (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Renal cell carcinoma, papillary, 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000838226.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004024373.2 First in ClinVar: Aug 13, 2023 Last updated: Aug 18, 2023
Likely benign (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Renal cell carcinoma Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000218519.11 First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024
Likely benign (Apr 29, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005075966.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024
Uncertain significance (Aug 07, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001782583.6 First in ClinVar: Aug 14, 2021 Last updated: Sep 16, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with lymphedema or breast cancer (PMID: 18564920, … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with lymphedema or breast cancer (PMID: 18564920, 35264596); This variant is associated with the following publications: (PMID: 24728327, 25637381, 32171644, 24339735, 30530636, 35264596, 18564920) (less)
Benign (Sep 11, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000673696.5 First in ClinVar: Apr 14, 2016 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 18564920‚ 24728327‚ 25637381 Comment: 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 … (more) 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. (less)
Likely benign (Jun 01, 2014)	no assertion criteria provided Method: research	Lymphoedema (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190329.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Likely benign (Aug 01, 2022)	no assertion criteria provided Method: clinical testing	MET-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004780290.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085525.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with lymphedema or breast cancer (PMID: 18564920, 35264596); This variant is associated with the following publications: (PMID: 24728327, 25637381, 32171644, 24339735, 30530636, 35264596, 18564920)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation.	Frayling IM	Journal of medical genetics	2019	PMID: 30530636
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
Identification of molecular tumor markers in renal cell carcinomas with TFE3 protein expression by RNA sequencing.	Pflueger D	Neoplasia (New York, N.Y.)	2013	PMID: 24339735
HGF and MET mutations in primary and secondary lymphedema.	Finegold DN	Lymphatic research and biology	2008	PMID: 18564920

Text-mined citations for rs180985111 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000245.4(MET):c.71G>A (p.Gly24Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs180985111 ...