VCV000267050.19 - ClinVar

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

Interpretation:: Pathogenic
Review status:: reviewed by expert panel
Submissions:: 7
First in ClinVar:: Oct 22, 2016
Most recent Submission:: Mar 4, 2023
Last evaluated:: Oct 18, 2016
Accession:: VCV000267050.19
Variation ID:: 267050
Description:: 1bp duplication

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

Allele ID

261447

Variant type

Duplication

Variant length

1 bp

Cytogenetic location

13q13.1

Genomic location

13: 32363217-32363218 (GRCh38) GRCh38 UCSC

13: 32937354-32937355 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.8021dup MANE Select	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

Canonical SPDI

NC_000013.11:32363217:AAAAAA:AAAAAAA

Functional consequence

Global minor allele frequency (GMAF)

Allele frequency

Links

ClinGen: CA10589464

dbSNP: rs397507952

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic	2	reviewed by expert panel	Oct 18, 2016	RCV000256831.6
Hereditary cancer-predisposing syndrome	Pathogenic	2	criteria provided, multiple submitters, no conflicts	Oct 6, 2020	RCV000563722.5
not provided	Pathogenic	1	criteria provided, single submitter	Jun 4, 2019	RCV000482911.4
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic	1	criteria provided, single submitter	Apr 2, 2020	RCV001310178.2
Hereditary breast ovarian cancer syndrome	Pathogenic	1	criteria provided, single submitter	Nov 2, 2021	RCV001222561.5

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	16959	17098

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Pathogenic (Oct 18, 2016)	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)	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 06, 2020)	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: SCV001736609.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 25203624, 29383094, 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)
Pathogenic (May 26, 2017)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000661432.4 First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022	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) Number of individuals with the variant: 1
Pathogenic (Oct 02, 2015)	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 (Nov 02, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Invitae Accession: SCV001394665.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	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 (Jun 04, 2019)	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)

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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 25203624, 29383094, 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.

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:

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)

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 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
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

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 Mar 26, 2023

ClinVar Genomic variation as it relates to human health

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

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

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs397507952...