rs80359675

Variant names:

• chr13-32331003-ACAAAT-A
• rs80359671
• NM_000059.4:c.771_775delTCAAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.771_775delTCAAA​(p.Asn257LysfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:33 O:1
• Conservation: PhyloP100: 2.46
• Publications: 23 publications found

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32331003-ACAAAT-A is Pathogenic according to our data. Variant chr13-32331003-ACAAAT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 9326.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.771_775delTCAAA	p.Asn257LysfsTer17	frameshift_variant	Exon 9 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.771_775delTCAAA	p.Asn257LysfsTer17	frameshift_variant	Exon 9 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.402_406delTCAAA	p.Asn134LysfsTer17	frameshift_variant	Exon 9 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.771_775delTCAAA		non_coding_transcript_exon_variant	Exon 8 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250748 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460348 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 726556

African (AFR) AF: 0.0000299 AC: 1 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110700

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:33 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:14

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Dec 19, 2016

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2023

deCODE genetics, Amgen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 15, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Oct 09, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM5_PTC_Strong -

May 27, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated, PP1 strong -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:6

Sep 29, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 09, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Hereditary breast ovarian cancer syndrome Pathogenic:5 Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Founder variant in Icelanders -

Sep 03, 2021

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 06, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.771_775delTCAAA pathogenic mutation, located in coding exon 8 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 771 to 775, causing a translational frameshift with a predicted alternate stop codon (p.N257Kfs*17). This mutation has been reported in several individuals diagnosed with breast and/or ovarian cancer (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7; Tryggvadottir L et al. Breast Cancer Res. Treat. 2013 Jul;140:375-84; Azzolllini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119). 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 S et al. Am. J. Hum. Genet. 1997 May;60:1079-84; Mikaelsdottir EK et al. Breast Cancer Res. 2004 Apr;6:R284-90). 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 JG et al. Br. J. Cancer 2016 Sep;115:776-83). Of note, this alteration is also designated as 999del5 in published literature. 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. -

Jun 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial cancer of breast Pathogenic:2

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Nov 24, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition Pathogenic:1

Mar 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

BRCA2-related disorder Pathogenic:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Breast carcinoma Pathogenic:1

Aug 08, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80359671; hg19: chr13-32905140;