VCV000009326.76 - ClinVar

NM_000059.4(BRCA2):c.771_775del (p.Asn257fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

34 submissions

34 submitters

8 conditions

Reviewed by expert panel

Pathogenic

Sep 2016 by Evidence-based…

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

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.771_775del (p.Asn257fs)

Variation ID: 9326 Accession: VCV000009326.76

Type and length

Deletion, 5 bp

Location

Cytogenetic: 13q13.1 13: 32331004-32331008 (GRCh38) [ NCBI UCSC ] 13: 32905141-32905145 (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 1, 2013	Oct 13, 2024	Sep 8, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.771_775del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Asn257fs	frameshift
NM_000059.3:c.771_775delTCAAA
NC_000013.11:g.32331008_32331012del
NC_000013.10:g.32905145_32905149del
NG_012772.3:g.20529_20533del
LRG_293:g.20529_20533del
U43746.1:n.999_1003delTCAAA

... more HGVS ... less HGVS

Protein change

Other names

995del5
999del5

Canonical SPDI

NC_000013.11:32331003:CAAATCAAA:CAAA

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

Breast Cancer Information Core (BIC) (BRCA2): 995&base_change=del CAAAT Breast Cancer Information Core (BIC) (BRCA2): 999&base_change=del TCAAA ClinGen: CA025222 OMIM: 600185.0010 dbSNP: rs80359671 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	18967	19126

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 (15)	reviewed by expert panel	Sep 8, 2016	RCV000009913.34
Familial cancer of breast	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 24, 2023	RCV000056288.21
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 12, 2024	RCV000131848.19
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000212208.28
Hereditary breast ovarian cancer syndrome	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 18, 2024	RCV000195405.25
BRCA2-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 30, 2024	RCV004732541.1
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (1)	criteria provided, single submitter	Apr 2, 2020	RCV001310167.9
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Aug 8, 2021	RCV001554244.9

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 (Sep 08, 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: SCV000300360.2 First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744392.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary Breast Carcinoma Affected status: unknown Allele origin: germline	GeneKor MSA Accession: SCV000693552.3 First in ClinVar: May 29, 2016 Last updated: May 04, 2020	Comment: This is a deletion of five base pairs, which results in frameshift and creation of a novel stop codon 17 amino acid residues later. The … (more) This is a deletion of five base pairs, which results in frameshift and creation of a novel stop codon 17 amino acid residues later. The result is a truncated, non-functional protein. Truncating variants in BRCA2 are known to be pathogenic.This variant is also known as 999del5 in the literature and is a common cause of breast and ovarian cancer in the Icelandic population but has been reported also in individuals of other ethnicities (PMID: 9150155, 8673089, 8589730 ; 25863477 ).The mutation database Clinvar contains entries for this variant (Variation ID:9326). (less)
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: SCV000327719.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010326.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Sep 29, 2020)	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: SCV000887922.3 First in ClinVar: Mar 13, 2019 Last updated: Jan 06, 2024	Publications: PubMed (23) PubMed: 15571962‚ 26689913‚ 27062684‚ 28724667‚ 29339979‚ 29625052‚ 29752822‚ 30350268‚ 30702160‚ 30720243‚ 30787465‚ 30875412‚ 31159747‚ 31825140‚ 32341426‚ 9802270‚ 8589730‚ 19478387‚ 23857704‚ 17591843‚ 9634522‚ 31957001‚ 30093976 Comment: This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, … (more) This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, the variant has been reported in individuals affected with breast cancer and has been described as a pathogenic founder variant in the Icelandic population (PMIDs: 31957001 (2020), 30093976 (2018), 23857704 (2013), and 17591843 (2007)). The frequency of this variant in the general population, 0.000092 (2/21636 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jan 18, 2024)	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: SCV000073307.13 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 28492532‚ 20104584‚ 8589730‚ 8673089‚ 9150155‚ 24549055‚ 25863477 Comment: This sequence change creates a premature translational stop signal (p.Asn257Lysfs17) 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.Asn257Lysfs17) 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 present in population databases (rs80359671, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 8589730, 8673089, 9150155, 24549055, 25863477). It is commonly reported in individuals of Icelandic ancestry (PMID: 8673089, 9150155). This variant is also known as 999del5. ClinVar contains an entry for this variant (Variation ID: 9326). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 18, 2023)	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: SCV004846823.1 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 (11) PubMed: 8673089‚ 9150155‚ 11781689‚ 12114473‚ 15217494‚ 15571962‚ 16768547‚ 23877192‚ 24156927‚ 24549055‚ 25863477 Comment: This variant deletes 5 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more) This variant deletes 5 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 999del5 and 995delCAAAT in the literature. This variant is expected to result in an absent protein product and transient expression of this variant protein in ex vivo cells showed that it was unstable (PMID: 15217494). This variant has been reported as an Iceland founder mutation where it segregates with female and male breast cancer in families (PMID: 8673089, 9150155). This variant is found to confer risk for breast cancer and ovarian cancer (PMID: 12114473, 15571962, 16768547). Haplotype analysis also suggests there are two common haplotypes for this variant in Finnish breast cancer affected families (PMID: 11781689). This variant also has been observed in breast and ovarian cancer affected individuals and families in Austria, Egypt, France and South Korea (PMID: 23877192, 24156927, 24549055, 25863477). This variant has been identified in 2/250748 chromosomes 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) Number of individuals with the variant: 1
Pathogenic (Sep 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	hereditary breast and ovarian cancer syndrome Affected status: unknown Allele origin: unknown	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV005045699.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024
Pathogenic (May 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV005045991.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Comment: PVS1; PM5_PTC_Strong
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002550262.6 First in ClinVar: Jul 30, 2022 Last updated: Aug 04, 2024
Pathogenic (Oct 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199574.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Department of Pathology and Laboratory Medicine, Sinai Health System Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000591710.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017
Pathogenic (Dec 09, 2015)	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: SCV001449839.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 3
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: SCV001499762.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Dec 19, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Medical Genetics, Oslo University Hospital Accession: SCV000605700.3 First in ClinVar: Mar 27, 2017 Last updated: Dec 11, 2022	Number of individuals with the variant: 6
Pathogenic (Jan 15, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488124.2 First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 10807692‚ 9150155‚ 23857704‚ 19478387‚ 8589730
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807465.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated, PP1 strong Number of individuals with the variant: 1 Clinical Features: Breast carcinoma (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Aug 01, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000210707.17 First in ClinVar: Feb 24, 2015 Last updated: Aug 13, 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; Published … (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; Published functional studies demonstrate a damaging effect: shown in expression studies to be extremely unstable and to impact cytokinesis (Mikaelsdottir et al., 2004; Jonsdottir et al., 2009); Reported as a founder pathogenic variant in Iceland, accounting for 7-8% of all breast and ovarian cancer in the country (Johannesdottir et al., 1996; Thorlacius et al., 1997; Jonsdottir et al., 2009); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Tavtigian et al., 1996; Thorlacius et al., 1997; Azzollini et al., 2017; Chan et al., 2018; Bhaskaran et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 999_1003del; This variant is associated with the following publications: (PMID: 28199346, 23857704, 8589730, 19478387, 8706004, 23747895, 9150155, 27537391, 28235830, 27062684, 29339979, 10807692, 30720243, 30702160, 30093976, 31159747, 31957001, 29625052, 26689913, 30787465, 31723001, 30350268, 31825140, 34254208, 32341426, 9802270, 30875412, 15571962, 34645131, 15217494) (less)
Pathogenic (Jul 06, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695095.2 First in ClinVar: Dec 26, 2017 Last updated: Aug 26, 2023	Publications: PubMed (8) PubMed: 19478387‚ 9643283‚ 9766673‚ 8706004‚ 15217494‚ 10807692‚ 16418514‚ 17565157 Comment: Variant summary: BRCA2 c.771_775delTCAAA (p.Asn257LysfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: BRCA2 c.771_775delTCAAA (p.Asn257LysfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250748 control chromosomes (gnomAD). c.771_775delTCAAA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Johannesdottir_1996 and Ingvarsson_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated variant affects normal protein expression (example: Mikaelsdottir_2004). The following publications have been ascertained in the context of this evaluation (PMID: 9766673, 8706004, 15217494). Eighteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 01, 2023)	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: SCV000683900.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (11) PubMed: 8673089‚ 9150155‚ 11781689‚ 12114473‚ 15217494‚ 15571962‚ 16768547‚ 23877192‚ 24156927‚ 24549055‚ 25863477 Comment: This variant deletes 5 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more) This variant deletes 5 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 999del5 and 995delCAAAT in the literature. This variant is expected to result in an absent protein product and transient expression of this variant protein in ex vivo cells showed that it was unstable (PMID: 15217494). This variant has been reported as an Iceland founder mutation where it segregates with female and male breast cancer in families (PMID: 8673089, 9150155). This variant is found to confer risk for breast cancer and ovarian cancer (PMID: 12114473, 15571962, 16768547). Haplotype analysis also suggests there are two common haplotypes for this variant in Finnish breast cancer affected families (PMID: 11781689). This variant also has been observed in breast and ovarian cancer affected individuals and families in Austria, Egypt, France and South Korea (PMID: 23877192, 24156927, 24549055, 25863477). This variant has been identified in 2/250748 chromosomes 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 (Feb 12, 2024)	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: SCV000186903.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 8589730‚ 9150155‚ 15217494‚ 23857704‚ 27062684‚ 27537391‚ 28724667 Comment: The c.771_775delTCAAA (p.N257Kfs17) alteration, located in exon 9 (coding exon 8) of the BRCA2 gene, consists of a deletion of 5 nucleotides from position 771 … (more) The c.771_775delTCAAA (p.N257Kfs17) alteration, located in exon 9 (coding exon 8) of the BRCA2 gene, consists of a deletion of 5 nucleotides from position 771 to 775, causing a translational frameshift with a predicted alternate stop codon after 17 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.001% (2/250748) total alleles studied. The highest observed frequency was <0.001% (2/21636) of alleles. This alteration has been reported in several individuals diagnosed with breast and/or ovarian cancer (Tavtigian, 1996; Tryggvadottir, 2013; Azzollini, 2016; Sun, 2017). This mutation has been described as an Icelandic founder mutation accounting for 7-8% of female breast cancer and 40% of male breast cancer in Iceland (Thorlacius, 1997; Mikaelsdottir, 2004). One Icelandic study comparing breast cancer patients with and without this mutation suggests that estrogen receptor status in carrier individuals is a factor affecting prognosis (Jonasson, 2016). Of note, this alteration is also designated as 999del5 in published literature. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Nov 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004213709.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Oct 09, 2012)	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: SCV000109205.2 First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014
Pathogenic (May 01, 2000)	no assertion criteria provided Method: literature only	BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030134.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 26, 2015	Publications: PubMed (2) PubMed: 9150155‚ 10807692 Comment on evidence: Thorlacius et al. (1997) found a 5-bp deletion in exon 9 starting at nucleotide 999 (999del5) and leading to early protein termination, in 16 of … (more) Thorlacius et al. (1997) found a 5-bp deletion in exon 9 starting at nucleotide 999 (999del5) and leading to early protein termination, in 16 of 21 Icelandic breast cancer families (BROVCA2; 612555), indicating a founder effect. They detected a 999del5 germline mutation in 0.6% of the Icelandic population, in 7.7% of female breast cancer patients, and in 40% of males with breast cancer. The mutation was strongly associated with onset of female breast cancer at age less than 50 years. A number of cancers other than breast cancer were found to be increased in relatives of mutation carriers, including those with prostate and pancreatic cancer. Comparison of the age at onset for mother/daughter pairs with the 999del5 mutation in breast cancer indicated that age at onset was decreasing in the younger generation. Increasing breast cancer incidence and lower age at onset suggested a possible contributing environmental factor. In Icelandic patients, Sigbjornsdottir et al. (2000) found loss of heterozygosity (LOH) at chromosome 8p in 50% of sporadic breast tumors and 78% of BRCA2-linked tumors carrying the 999del5 mutation. The pattern of LOH was different in the 2 groups with a high proportion of BRCA2 tumors having LOH in a large region of chromosome 8p. Patients with LOH at 8p have a worse prognosis than patients without this defect. Multivariate analysis suggested that LOH at 8p is an independent prognostic factor. Sigbjornsdottir et al. (2000) concluded that chromosome 8p carries a tumor suppressor gene(s), the loss of which results in growth advantage of breast tumor cells, especially in carriers of the BRCA2 999del5 mutation. (less)
Pathogenic (May 24, 2021)	no assertion criteria provided Method: case-control	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) Accession: SCV005061311.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Publications: PubMed (1) PubMed: 38922859 Secondary finding: no
Pathogenic (May 29, 2002)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline, unknown	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000147710.2 First in ClinVar: Apr 01, 2014 Last updated: Oct 11, 2015	Observation 1: Number of individuals with the variant: 3 Observation 2: Number of individuals with the variant: 1 Geographic origin: English, Icelandic Observation 3: Number of individuals with the variant: 1 Ethnicity/Population group: Central/Eastern European Observation 4: Number of individuals with the variant: 2 Ethnicity/Population group: Latin American, Caribbean Observation 5: Number of individuals with the variant: 1 Ethnicity/Population group: Latin American, Caribbean, Cuban Observation 6: Number of individuals with the variant: 1 Ethnicity/Population group: Native American Observation 7: Number of individuals with the variant: 1 Ethnicity/Population group: Native American, Central/Eastern European, L Observation 8: Number of individuals with the variant: 3 Ethnicity/Population group: Western European Observation 9: Number of individuals with the variant: 1
Pathogenic (Jan 31, 2014)	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: SCV000587570.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733217.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Aug 08, 2021)	no assertion criteria provided Method: clinical testing	Breast carcinoma (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001774821.1 First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021	Indication for testing: breast cancer Sex: male Comment on evidence: Invasive breast carcinoma EST receptor + PRO receptor + HER2 receptor +
Pathogenic (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002588850.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Jul 21, 2023)	no assertion criteria provided Method: research	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	deCODE genetics, Amgen Accession: SCV004022192.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: The variant NM_000059.4:c.771_775del (chr13:32331003) in BRCA2 was detected in 421 heterozygotes out of 58K WGS Icelanders (MAF= 0,363%). Following imputation in a set of 166K … (more) The variant NM_000059.4:c.771_775del (chr13:32331003) in BRCA2 was detected in 421 heterozygotes out of 58K WGS Icelanders (MAF= 0,363%). Following imputation in a set of 166K Icelanders (1,161 imputed heterozygotes) we observed an association with breast cancer using 6908 cases and 292623 controls (OR= 17.14, P= 1.37e-172). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. (less) Number of individuals with the variant: 1161 Ethnicity/Population group: Icelandic
Pathogenic (Jul 30, 2024)	no assertion criteria provided Method: clinical testing	BRCA2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005364793.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The BRCA2 c.771_775del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn257Lysfs17). This variant (also reported as c.999del5) has been reported … (more) The BRCA2 c.771_775del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn257Lysfs17). This variant (also reported as c.999del5) has been reported to be causative for breast and ovarian cancer (Tavtigian et al. 1996. PubMed ID: 8589730; Kang et al. 2015. PubMed ID: 25863477; Castéra et al. 2014. PubMed ID: 24549055) and is considered an Icelandic pathogenic founder variant associated with breast and ovarian cancers (Thorlacius et al. 1996. PubMed ID: 8673089; Thorlacius et al. 1997. PubMed ID: 9150155). This variant is reported in 0.0092% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000086655.3 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 15571962 BookShelf: NBK1247 BookShelf: NBK1247 Comment: Founder variant in Icelanders
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Comment:

This is a deletion of five base pairs, which results in frameshift and creation of a novel stop codon 17 amino acid residues later. The result is a truncated, non-functional protein. Truncating variants in BRCA2 are known to be pathogenic.This variant is also known as 999del5 in the literature and is a common cause of breast and ovarian cancer in the Icelandic population but has been reported also in individuals of other ethnicities (PMID: 9150155, 8673089, 8589730 ; 25863477 ).The mutation database Clinvar contains entries for this variant (Variation ID:9326).

Comment:

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, the variant has been reported in individuals affected with breast cancer and has been described as a pathogenic founder variant in the Icelandic population (PMIDs: 31957001 (2020), 30093976 (2018), 23857704 (2013), and 17591843 (2007)). The frequency of this variant in the general population, 0.000092 (2/21636 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Asn257Lysfs*17) 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 present in population databases (rs80359671, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 8589730, 8673089, 9150155, 24549055, 25863477). It is commonly reported in individuals of Icelandic ancestry (PMID: 8673089, 9150155). This variant is also known as 999del5. ClinVar contains an entry for this variant (Variation ID: 9326). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant deletes 5 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 999del5 and 995delCAAAT in the literature. This variant is expected to result in an absent protein product and transient expression of this variant protein in ex vivo cells showed that it was unstable (PMID: 15217494). This variant has been reported as an Iceland founder mutation where it segregates with female and male breast cancer in families (PMID: 8673089, 9150155). This variant is found to confer risk for breast cancer and ovarian cancer (PMID: 12114473, 15571962, 16768547). Haplotype analysis also suggests there are two common haplotypes for this variant in Finnish breast cancer affected families (PMID: 11781689). This variant also has been observed in breast and ovarian cancer affected individuals and families in Austria, Egypt, France and South Korea (PMID: 23877192, 24156927, 24549055, 25863477). This variant has been identified in 2/250748 chromosomes 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:

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; Published functional studies demonstrate a damaging effect: shown in expression studies to be extremely unstable and to impact cytokinesis (Mikaelsdottir et al., 2004; Jonsdottir et al., 2009); Reported as a founder pathogenic variant in Iceland, accounting for 7-8% of all breast and ovarian cancer in the country (Johannesdottir et al., 1996; Thorlacius et al., 1997; Jonsdottir et al., 2009); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Tavtigian et al., 1996; Thorlacius et al., 1997; Azzollini et al., 2017; Chan et al., 2018; Bhaskaran et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 999_1003del; This variant is associated with the following publications: (PMID: 28199346, 23857704, 8589730, 19478387, 8706004, 23747895, 9150155, 27537391, 28235830, 27062684, 29339979, 10807692, 30720243, 30702160, 30093976, 31159747, 31957001, 29625052, 26689913, 30787465, 31723001, 30350268, 31825140, 34254208, 32341426, 9802270, 30875412, 15571962, 34645131, 15217494)

Comment:

Variant summary: BRCA2 c.771_775delTCAAA (p.Asn257LysfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250748 control chromosomes (gnomAD). c.771_775delTCAAA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Johannesdottir_1996 and Ingvarsson_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated variant affects normal protein expression (example: Mikaelsdottir_2004). The following publications have been ascertained in the context of this evaluation (PMID: 9766673, 8706004, 15217494). Eighteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The c.771_775delTCAAA (p.N257Kfs*17) alteration, located in exon 9 (coding exon 8) of the BRCA2 gene, consists of a deletion of 5 nucleotides from position 771 to 775, causing a translational frameshift with a predicted alternate stop codon after 17 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.001% (2/250748) total alleles studied. The highest observed frequency was <0.001% (2/21636) of alleles. This alteration has been reported in several individuals diagnosed with breast and/or ovarian cancer (Tavtigian, 1996; Tryggvadottir, 2013; Azzollini, 2016; Sun, 2017). This mutation has been described as an Icelandic founder mutation accounting for 7-8% of female breast cancer and 40% of male breast cancer in Iceland (Thorlacius, 1997; Mikaelsdottir, 2004). One Icelandic study comparing breast cancer patients with and without this mutation suggests that estrogen receptor status in carrier individuals is a factor affecting prognosis (Jonasson, 2016). Of note, this alteration is also designated as 999del5 in published literature. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The variant NM_000059.4:c.771_775del (chr13:32331003) in BRCA2 was detected in 421 heterozygotes out of 58K WGS Icelanders (MAF= 0,363%). Following imputation in a set of 166K Icelanders (1,161 imputed heterozygotes) we observed an association with breast cancer using 6908 cases and 292623 controls (OR= 17.14, P= 1.37e-172). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic.

Comment:

The BRCA2 c.771_775del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn257Lysfs*17). This variant (also reported as c.999del5) has been reported to be causative for breast and ovarian cancer (Tavtigian et al. 1996. PubMed ID: 8589730; Kang et al. 2015. PubMed ID: 25863477; Castéra et al. 2014. PubMed ID: 24549055) and is considered an Icelandic pathogenic founder variant associated with breast and ovarian cancers (Thorlacius et al. 1996. PubMed ID: 8673089; Thorlacius et al. 1997. PubMed ID: 9150155). This variant is reported in 0.0092% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted 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
Featuring BRCA1 and BRCA2 germline mutational landscape from Asturias (North Spain).	Pitiot AS	Clinical genetics	2024	PMID: 38922859
BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.	Adam MP	-	2023	PMID: 20301425
Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.	De Talhouet S	Scientific reports	2020	PMID: 32341426
BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients.	Meng H	International journal of cancer	2020	PMID: 31957001
Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients.	Gao X	Human mutation	2020	PMID: 31825140
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747
Discoveries beyond BRCA1/2: Multigene testing in an Asian multi-ethnic cohort suspected of hereditary breast cancer syndrome in the real world.	Ow SGW	PloS one	2019	PMID: 30875412
Toward automation of germline variant curation in clinical cancer genetics.	Ravichandran V	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30787465
High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.	Soussi T	Human mutation	2019	PMID: 30720243
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
Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea.	Ryu JM	Breast cancer research and treatment	2019	PMID: 30350268
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
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.	Chan GHJ	Oncotarget	2018	PMID: 30093976
Pathogenic Germline Variants in 10,389 Adult Cancers.	Huang KL	Cell	2018	PMID: 29625052
BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway.	Heramb C	Hereditary cancer in clinical practice	2018	PMID: 29339979
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
Oestrogen receptor status, treatment and breast cancer prognosis in Icelandic BRCA2 mutation carriers.	Jonasson JG	British journal of cancer	2016	PMID: 27537391
Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study.	Azzollini J	European journal of internal medicine	2016	PMID: 27062684
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study.	Kang E	Breast cancer research and treatment	2015	PMID: 25863477
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes.	Castéra L	European journal of human genetics : EJHG	2014	PMID: 24549055
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer.	Tea MK	Maturitas	2014	PMID: 24156927
Detection of new point mutations of BRCA1 and BRCA2 in breast cancer patients.	Bensam M	Biochemical genetics	2014	PMID: 23877192
Tumour diploidy and survival in breast cancer patients with BRCA2 mutations.	Tryggvadottir L	Breast cancer research and treatment	2013	PMID: 23857704
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
BRCA2 heterozygosity delays cytokinesis in primary human fibroblasts.	Jonsdottir AB	Cellular oncology : the official journal of the International Society for Cellular Oncology	2009	PMID: 19478387
Founder mutations in BRCA1 and BRCA2 genes.	Ferla R	Annals of oncology : official journal of the European Society for Medical Oncology	2007	PMID: 17591843
Prostate cancer progression and survival in BRCA2 mutation carriers.	Tryggvadóttir L	Journal of the National Cancer Institute	2007	PMID: 17565157
The BARD1 Cys557Ser variant and breast cancer risk in Iceland.	Stacey SN	PLoS medicine	2006	PMID: 16768547
Population-based study of changing breast cancer risk in Icelandic BRCA2 mutation carriers, 1920-2000.	Tryggvadottir L	Journal of the National Cancer Institute	2006	PMID: 16418514
BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: a population-based study.	Rafnar T	European journal of cancer (Oxford, England : 1990)	2004	PMID: 15571962
The Icelandic founder mutation BRCA2 999del5: analysis of expression.	Mikaelsdottir EK	Breast cancer research : BCR	2004	PMID: 15217494
The effect of a single BRCA2 mutation on cancer in Iceland.	Tulinius H	Journal of medical genetics	2002	PMID: 12114473
Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.	Barkardottir RB	European journal of human genetics : EJHG	2001	PMID: 11781689
Chromosome 8p alterations in sporadic and BRCA2 999del5 linked breast cancer.	Sigbjörnsdottir BI	Journal of medical genetics	2000	PMID: 10807692
Population-based study of risk of breast cancer in carriers of BRCA2 mutation.	Thorlacius S	Lancet (London, England)	1998	PMID: 9802270
High incidence of loss of heterozygosity in breast tumors from carriers of the BRCA2 999del5 mutation.	Ingvarsson S	Cancer research	1998	PMID: 9766673
A population study of mutations and LOH at breast cancer gene loci in tumours from sister pairs: two recurrent mutations seem to account for all BRCA1/BRCA2 linked breast cancer in Iceland.	Arason A	Journal of medical genetics	1998	PMID: 9643283
The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction.	Lerer I	American journal of human genetics	1998	PMID: 9634522
Study of a single BRCA2 mutation with high carrier frequency in a small population.	Thorlacius S	American journal of human genetics	1997	PMID: 9150155
High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients.	Johannesdottir G	Cancer research	1996	PMID: 8706004
A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes.	Thorlacius S	Nature genetics	1996	PMID: 8673089
The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.	Tavtigian SV	Nature genetics	1996	PMID: 8589730
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Text-mined citations for rs80359671 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.771_775del (p.Asn257fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359671 ...