VCV000051135.43 - ClinVar

NM_000059.4(BRCA2):c.1499del (p.Gly500fs)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Breast-ovarian cancer, familial, susceptibility to, 2

Classification is based on the expert panel submission

Sep 2016 by Evidence-based Network for the Interpretation of Germline M…

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.1499del (p.Gly500fs)

Variation ID: 51135 Accession: VCV000051135.43

Type and length

Deletion, 1 bp

Location

Cytogenetic: 13q13.1 13: 32332975 (GRCh38) [ NCBI UCSC ] 13: 32907112 (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	Sep 27, 2014	May 25, 2025	Sep 8, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.1499del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Gly500fs	frameshift
NM_000059.3:c.1499delG
NC_000013.11:g.32332977del
NC_000013.10:g.32907114del
NG_012772.3:g.22498del
LRG_293:g.22498del

... more HGVS ... less HGVS

Protein change

Other names

1727delG

Canonical SPDI

NC_000013.11:32332974:GGG:GG

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.

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

Links

ClinGen: CA012235 dbSNP: rs397507591 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.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	19967	20129

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.
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (4)	reviewed by expert panel	Sep 8, 2016	RCV000077258.15
Hereditary breast ovarian cancer syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 1, 2025	RCV000496652.20
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jun 3, 2022	RCV000565720.11
Ovarian neoplasm	Pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785214.10
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 19, 2025	RCV001269907.30

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.
Pathogenic (Sep 08, 2016) C Contributing to aggregate classification	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015)) Method: curation	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV000300434.2 First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.

Pathogenic (Dec 23, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hereditary breast ovarian cancer syndrome (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000605809.2 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017	Publications: PubMed (1) PubMed: 11802209 Comment: The p.Gly500fs variant in BRCA2 has been reported in at least 2 individuals with BRCA2-associated cancers (Meindl 2002) and was absent from large population stu … (more) The p.Gly500fs variant in BRCA2 has been reported in at least 2 individuals with BRCA2-associated cancers (Meindl 2002) and was absent from large population stu dies. The p.Gly500fs variant is predicted to cause a frameshift, which alters t he protein?s amino acid sequence beginning at position 500 and leads to a premat ure termination codon 9 amino acids downstream. This alteration is then predicte d to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on Septem ber 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300434.2) . In summary, this variant meets criteria to be classified as pathogenic for HBO C in an autosomal dominant manner based upon segregation studies and the predict ed impact to the protein. (less) Number of individuals with the variant: 1

Pathogenic (Dec 11, 2014) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450262.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 5

Pathogenic (Dec 13, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001470196.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (3) PubMed: 30702160‚ 11802209‚ 19941162 Comment: The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in … (more) The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. (less)

Pathogenic (Jun 03, 2022) N Not contributing to aggregate classification	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: SCV000668865.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 11802209‚ 19941162 Comment: The c.1499delG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1499, causing … (more) The c.1499delG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1499, causing a translational frameshift with a predicted alternate stop codon (p.G500Vfs*9). This alteration, designated 1727delG, was detected in 2/989 unrelated individuals from a cohort of German breast/ovarian cancer families (Meindl A et al. Int. J. Cancer, 2002 Feb;97:472-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)

Pathogenic (Jan 01, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000959498.7 First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 20104584‚ 11802209 Comment: This sequence change creates a premature translational stop signal (p.Gly500Valfs9) in the BRCA2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gly500Valfs9) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 11802209). This variant is also known as 1727delG. ClinVar contains an entry for this variant (Variation ID: 51135). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. (less)

Pathogenic (Sep 15, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001905529.2 First in ClinVar: Sep 25, 2021 Last updated: Apr 13, 2025	Clinical Features: Breast carcinoma (present) Sex: female

Pathogenic (Aug 01, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002822064.18 First in ClinVar: Jan 21, 2023 Last updated: May 25, 2025	Comment: BRCA2: PVS1, PM2 Number of individuals with the variant: 6

Pathogenic (May 19, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002820717.2 First in ClinVar: Jan 21, 2023 Last updated: May 25, 2025	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1727delG; This variant is associated with the following publications: (PMID: 31825140, 19941162, 20104584, JiangY2021[preprint], 30702160, 34308104, 29053726, 11802209) (less)

Pathogenic (Oct 02, 2015) N Not contributing to aggregate classification	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge Accession: SCV000326561.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022

Pathogenic (Feb 03, 2009) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: not provided Allele origin: germline	Sharing Clinical Reports Project (SCRP) Accession: SCV000109055.2 First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014

Pathogenic (Jan 31, 2014) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000587599.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017

Pathogenic (Mar 02, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV004244220.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024

Pathogenic (Dec 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Ovarian neoplasm Affected status: yes Allele origin: germline	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne Accession: SCV000923782.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019

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Comment:

The p.Gly500fs variant in BRCA2 has been reported in at least 2 individuals with BRCA2-associated cancers (Meindl 2002) and was absent from large population stu dies. The p.Gly500fs variant is predicted to cause a frameshift, which alters t he protein?s amino acid sequence beginning at position 500 and leads to a premat ure termination codon 9 amino acids downstream. This alteration is then predicte d to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on Septem ber 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300434.2) . In summary, this variant meets criteria to be classified as pathogenic for HBO C in an autosomal dominant manner based upon segregation studies and the predict ed impact to the protein.

Comment:

The c.1499delG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1499, causing a translational frameshift with a predicted alternate stop codon (p.G500Vfs*9). This alteration, designated 1727delG, was detected in 2/989 unrelated individuals from a cohort of German breast/ovarian cancer families (Meindl A et al. Int. J. Cancer, 2002 Feb;97:472-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change creates a premature translational stop signal (p.Gly500Valfs*9) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 11802209). This variant is also known as 1727delG. ClinVar contains an entry for this variant (Variation ID: 51135). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1727delG; This variant is associated with the following publications: (PMID: 31825140, 19941162, 20104584, JiangY2021[preprint], 30702160, 34308104, 29053726, 11802209)

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
Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients.	Bhaskaran SP	International journal of cancer	2019	PMID: 30702160
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.	Borg A	Human mutation	2010	PMID: 20104584
High-throughput resequencing in the diagnosis of BRCA1/2 mutations using oligonucleotide resequencing microarrays.	Schroeder C	Breast cancer research and treatment	2010	PMID: 19941162
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.	Meindl A	International journal of cancer	2002	PMID: 11802209

Text-mined citations for rs397507591 ...

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 May 25, 2025

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.1499del (p.Gly500fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397507591 ...