rs80359705

Variant names:

• chr13-32363498-AC-A
• rs80359705
• NM_000059.4:c.8297delC

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.8297delC​(p.Thr2766AsnfsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000112 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T2766T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:27
• Conservation: PhyloP100: 4.71
• 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 13-32363498-AC-A is Pathogenic according to our data. Variant chr13-32363498-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38149.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.8297delC	p.Thr2766AsnfsTer11	frameshift_variant	Exon 18 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8297delC	p.Thr2766AsnfsTer11	frameshift_variant	Exon 18 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7928delC	p.Thr2643AsnfsTer11	frameshift_variant	Exon 18 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*355delC		non_coding_transcript_exon_variant	Exon 17 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*355delC		3_prime_UTR_variant	Exon 17 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111950

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 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 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 9 individuals affected with breast or ovarian cancer (PMID: 10682686, 12960223, 23146383, 25682074, 26681312, 26845104, 33471991), 3 individuals affected with prostate cancer (PMID: 20736950, 23569316), and 1 unaffected individual (PMID: 33471991). This variant has been identified in 70 families among the CIMBA participants (PMID: 29446198). 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. -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Apr 16, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 22, 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. -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

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

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 29, 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.Thr2766Asnfs*11) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, ovarian and/or prostate cancer (PMID: 8589730, 10682686, 12960223, 20736950, 23028338, 25085752, 26681312). This variant is also known as 8525delC. ClinVar contains an entry for this variant (Variation ID: 38149). For these reasons, this variant has been classified as Pathogenic. -

Feb 22, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr2766AsnfsX11 (NM_000059.3 c.8297delC) variant in BRCA2 (also referred t o as c.8285delC in the literature) has been previously reported in many individu als and families with breast, ovarian or prostate cancer (Tavtigian 1996, Castro 2013, McVeigh 2014, Wong-Brown 2015), and was absent from large population stud ies. In addition, this variant was classified as Pathogenic by the ClinGen-appr oved ENIGMA expert panel (ClinVar SCV000282457.1). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2766 and leads to a premature termination codon 11 amino acids downstre am. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in here ditary breast and ovarian cancer syndrome (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant m anner based on its occurrence in affected individuals and its predicted impact t o the protein. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PP5 (Richards 2015). -

Jul 01, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA2 c.8297delC (p.Thr2766Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP). Multiple publications cite the variant in affected individuals, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -

not provided Pathogenic:4

Apr 13, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.8297del; p.Thr2766AsnfsTer11 variant (rs80359705), also known as 8525delC, is reported in individuals with hereditary breast and ovarian cancer syndrome (Edwards 2010, Lilyquist 2017, Tavtigian 1996). This variant is also reported in ClinVar (Variation ID: 38149). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Edwards SM et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. PMID: 20736950. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Tavtigian SV et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333-7. PMID: 8589730. -

Jan 27, 2022

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; Observed in individuals with a personal and/or family history of BRCA2-related cancers (Tavtigian 1996, Evans 2003, Edwards 2010, Willems-Jones 2012, McVeigh 2014, Pritzlaff 2017); 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 8525delC; This variant is associated with the following publications: (PMID: 12474142, 20736950, 12960223, 30609409, 12181777, 26046366, 25682074, 26681312, 23035815, 23884708, 8589730, 23028338, 28008555, 25085752, 22703879, 26845104, 31090900, 26295337, 25685387, 23569316, 10682686, 31569370, 32853339, 30787465, 33087929) -

Sep 12, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.8297del (p.Thr2766Asnfs*11) variant has been reported in the published literature in individuals and families affected with breast and/or ovarian cancer (PMIDs: 8589730 (1996), 10682686 (2000), 26681312 (2015)) and prostate cancer (PMIDs: 20736950 (2010), 23569316 (2013)). The frequency of this variant in the general population, 0.0000066 (1/152178 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:4

Sep 01, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 23, 2018

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 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 9 individuals affected with breast or ovarian cancer (PMID: 10682686, 12960223, 23146383, 25682074, 26681312, 26845104, 33471991), 3 individuals affected with prostate cancer (PMID: 20736950, 23569316), and 1 unaffected individual (PMID: 33471991). This variant has been identified in 70 families among the CIMBA participants (PMID: 29446198). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 97.89 from log(LR)=1.990739107 for 13 carriers (PMID: 31853058). 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. -

Dec 23, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8297delC pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 8297, causing a translational frameshift with a predicted alternate stop codon (p.T2766Nfs*11). This mutation was reported in one family with multiple cases of female and male breast cancer and ovarian cancer (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7). This alteration has also been reported in multiple men diagnosed with prostate cancer before the age of 55 (Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Willems-Jones A et al. BJU Int. 2012 Dec;110:E1181-6; Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57). Of note, this alteration is also designated as 8525delC 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Mar 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Pathogenic:1

Nov 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.8297delC variant is predicted to result in a frameshift and premature protein termination (p.Thr2766Asnfs*11). This variant (also known as 8525delC) has been reported in individuals with breast, ovarian, or prostate cancer (Table 1, Tavtigian et al. 1996. PubMed ID: 8589730; Table 1, Edwards et al. 2003. PubMed ID: 12474142; Table 1, Edwards et al. 2010. PubMed ID: 20736950, Table 2, Wong-Brown et al. 2015. PubMed ID: 25682074; Table S7, Lilyquist et al. 2017. PubMed ID: 28888541). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been reviewed by an expert panel and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38149/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Feb 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1

Feb 10, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80359705; hg19: chr13-32937635; COSMIC: COSV66450547; COSMIC: COSV66450547;