VCV000267050.26 - ClinVar

NM_000059.4(BRCA2):c.8021dup (p.Ile2675fs)

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

Oct 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.8021dup (p.Ile2675fs)

Variation ID: 267050 Accession: VCV000267050.26

Type and length

Duplication, 1 bp

Location

Cytogenetic: 13q13.1 13: 32363217-32363218 (GRCh38) [ NCBI UCSC ] 13: 32937354-32937355 (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	Oct 22, 2016	May 3, 2025	Oct 18, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.8021dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Ile2675fs	frameshift
NM_000059.3:c.8021dupA
NC_000013.11:g.32363223dup
NC_000013.10:g.32937360dup
NG_012772.3:g.52744dup
LRG_293:g.52744dup

... more HGVS ... less HGVS

Protein change

I2675fs

Other names

8249insA
p.Ile2675Aspfs*6

Canonical SPDI

NC_000013.11:32363217:AAAAAA:AAAAAAA

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: CA10589464 dbSNP: rs397507952 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	19963	20125

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 (3)	reviewed by expert panel	Oct 18, 2016	RCV000256831.15
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 5, 2023	RCV000482911.12
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 11, 2024	RCV000563722.15
Hereditary breast ovarian cancer syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 9, 2024	RCV001222561.15
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (1)	criteria provided, single submitter	Apr 2, 2020	RCV001310178.9

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 (Oct 18, 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: SCV000324614.2 First in ClinVar: Oct 22, 2016 Last updated: Feb 07, 2023	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (Apr 02, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499773.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
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: SCV000327799.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (Jun 04, 2019) 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: SCV000565763.6 First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023	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 … (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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24755471, 23047548, 26787237, 29752822, 30078507, 31825140) (less)
Pathogenic (Dec 06, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004845589.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (5) PubMed: 8988179‚ 11897832‚ 29383094‚ 29446198‚ 30078507 Comment: The c.8021dup (p.Ile2675Aspfs6) variant in the BRCA2 gene is located on the exon 18 and is predicted to result in a frameshift that introduces a … (more) The c.8021dup (p.Ile2675Aspfs6) variant in the BRCA2 gene is located on the exon 18 and is predicted to result in a frameshift that introduces a premature translation termination codon, resulting in an absent or disrupted protein product. This variant has been identified in individuals with breast or ovarian cancer (PMID: 30078507, 29383094). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 267050) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.8021dup (p.Ile2675Aspfs*6) variant in the BRCA2 gene has been classified as pathogenic. (less) Number of individuals with the variant: 1 Zygosity: Single Heterozygote
Pathogenic (Nov 07, 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: SCV000661432.6 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 26787237 Comment: The c.8021dupA pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a duplication of A at nucleotide position 8021, causing a … (more) The c.8021dupA pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a duplication of A at nucleotide position 8021, causing a translational frameshift with a predicted alternate stop codon (p.I2675Dfs*6). This mutation (designated c.8015_8016insA) was identified in an individual with head and neck cancer and no family history of cancer (Meric-Bernstam F et al. Ann. Oncol. 2016 May;27:795-800). 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 (Dec 05, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414165.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 29752822‚ 30078507 Comment: PM2, PM5_strong, PVS1 Number of individuals with the variant: 1
Pathogenic (Dec 09, 2024) 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: SCV001394665.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025	Publications: PubMed (5) PubMed: 20104584‚ 26787237‚ 29383094‚ 29752822‚ 30078507 Comment: This sequence change creates a premature translational stop signal (p.Ile2675Aspfs6) 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.Ile2675Aspfs6) 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 head and neck cancer and breast and/or ovarian cancer (PMID: 26787237, 29383094, 29752822, 30078507). This variant is also known as c.8016dupA or c.8015_8016insA. ClinVar contains an entry for this variant (Variation ID: 267050). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 11, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001736609.2 First in ClinVar: Jun 19, 2021 Last updated: May 03, 2025	Publications: PubMed (3) PubMed: 29383094‚ 29752822‚ 30078507 Comment: This variant inserts 1 nucleotide in exon 18 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant inserts 1 nucleotide in exon 18 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 3 individuals affected with breast or ovarian cancer (PMID: 29383094, 30078507, 29752822). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)

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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24755471, 23047548, 26787237, 29752822, 30078507, 31825140)

Comment:

The c.8021dup (p.Ile2675Aspfs*6) variant in the BRCA2 gene is located on the exon 18 and is predicted to result in a frameshift that introduces a premature translation termination codon, resulting in an absent or disrupted protein product. This variant has been identified in individuals with breast or ovarian cancer (PMID: 30078507, 29383094). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 267050) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.8021dup (p.Ile2675Aspfs*6) variant in the BRCA2 gene has been classified as pathogenic.

Comment:

The c.8021dupA pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a duplication of A at nucleotide position 8021, causing a translational frameshift with a predicted alternate stop codon (p.I2675Dfs*6). This mutation (designated c.8015_8016insA) was identified in an individual with head and neck cancer and no family history of cancer (Meric-Bernstam F et al. Ann. Oncol. 2016 May;27:795-800). 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.Ile2675Aspfs*6) 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 head and neck cancer and breast and/or ovarian cancer (PMID: 26787237, 29383094, 29752822, 30078507). This variant is also known as c.8016dupA or c.8015_8016insA. ClinVar contains an entry for this variant (Variation ID: 267050). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant inserts 1 nucleotide in exon 18 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 3 individuals affected with breast or ovarian cancer (PMID: 29383094, 30078507, 29752822). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

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 mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.	Li JY	International journal of cancer	2019	PMID: 29752822
BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls.	Li A	Gynecologic oncology	2018	PMID: 30078507
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
Simultaneous detection of genetic and copy number alterations in BRCA1/2 genes.	Hirotsu Y	Oncotarget	2017	PMID: 29383094
Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol.	Meric-Bernstam F	Annals of oncology : official journal of the European Society for Medical Oncology	2016	PMID: 26787237
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
Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany.	Hamann U	Journal of medical genetics	2002	PMID: 11897832
Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.	Gayther SA	Nature genetics	1997	PMID: 8988179

Text-mined citations for rs397507952 ...

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 03, 2025

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.8021dup (p.Ile2675fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397507952 ...