13-32332778-AAAAGAAAG-AAAAGAAAGAAAG

Variant names:

• chr13-32332778-A-AAAAG
• rs80359277
• NM_000059.4:c.1310_1313dupAAGA

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_SupportingO2_Very_StrongO3_Moderate

The NM_000059.4(BRCA2):c.1310_1313dupAAGA (p.Asp438GlufsTer15) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The gene BRCA2 is a tumor suppressor gene (CancerMine: 139 TSG, 7 oncogene, 19 driver citations). The gene BRCA2 is a cancer driver gene (CancerMine: 139 TSG, 7 oncogene, 19 driver citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.22
• Publications: 9 publications found

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) The product of this gene in involved in maintenance of genome stability. It is involved in double-strand break repair pathways during mitotic and meiotic homologous recombination and functions in protecting DNA replication forks. The encoded protein contains sites for interactions with PALB2 and EMSY and an N-terminal DNA binding domain. It also contains a RAD51 binding domain with multiple components. It has multiple BRC repeats, an alpha helix domain, oligonucleotide binding folds, and a tower-like domain. It has a nuclear localization signal and a phosphorylation site for cyclin-dependent kinase. The C-terminus of the protein can bind single-stranded and double-stranded DNA. The product of this gene interacts with multiple proteins, including RAD51. It is involved in recruiting RAD51 filaments to DNA double-strand break sites and also in cytoplasmic division. It also acts as a tumor suppressor. Mutations in this gene or decreased expression have been implicated in multiple tumor types, including breast, ovarian, pancreatic, prostate and other cancers. [provided by RefSeq, May 2026]

BRCA2 Gene-Disease associations (from GenCC):

• BRCA2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 2

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP (single/no review) — Supporting (O1); O1 contributing sources (1.0 pts): ClinVar germline P/LP in TSG (★)
	O2Null variant in tumour suppressor gene		Frameshift/stop-gained, NMD predicted, LoF oncogenic mechanism — O2 very strong (+8); Use caution in the presence of multiple transcripts; Gene confirmed as TSG in CancerMine (TSG: 139 citations, oncogene: 7 citations, driver: 19 citations).; Frameshift/stop-gained. NMD predicted: true. LoF mechanism: true. Downstream pathogenic count: 4911.
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA2 NM_000059.4	MANE Select	c.1310_1313dupAAGA p.Asp438GlufsTer15	frameshift	Exon 10 of 27	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.1310_1313dupAAGA p.Asp438GlufsTer15	frameshift	Exon 10 of 27	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.1310_1313dupAAGA p.Asp438GlufsTer15	frameshift	Exon 10 of 27	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.1310_1313dupAAGAp.Asp438GlufsTer15

Exon rankExon 10 of 27

frameshift

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.1310_1313dupAAGAp.Asp438GlufsTer15

Exon rankExon 10 of 27

frameshift

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.1310_1313dupAAGAp.Asp438GlufsTer15

Exon rankExon 10 of 27

frameshift

Prot: NP_001393649.1UniProt: A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA2 ENST00000380152.8	TSL:5MANE Select	c.1310_1313dupAAGA p.Asp438GlufsTer15	frameshift	Exon 10 of 27	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.1310_1313dupAAGA p.Asp438GlufsTer15	frameshift	Exon 10 of 27	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.941_944dupAAGA p.Asp315GlufsTer15	frameshift	Exon 10 of 27	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.1310_1313dupAAGAp.Asp438GlufsTer15

Exon rankExon 10 of 27

frameshift

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.1310_1313dupAAGAp.Asp438GlufsTer15

Exon rankExon 10 of 27

frameshift

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.941_944dupAAGAp.Asp315GlufsTer15

Exon rankExon 10 of 27

frameshift

Prot: ENSP00000499438.2UniProt: A0A590UJI7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	1.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs80359277;

hg19: chr13-32906915;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar