13-32333283-GA-G

Variant names:

• chr13-32333283-GA-G
• rs80359306
• NM_000059.4:c.1813delA

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_ModerateO2_Very_StrongO3_ModerateO4_Moderate

The NM_000059.4(BRCA2):c.1813delA (p.Ile605TyrfsTer9) 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). The variant allele was found at a cumulative frequency of 0.0000066 (AC=1) in the gnomAD database across 151,588 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000193. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). The variant has been observed in cBioPortal in 77 samples across 26 studies and 18 cancer types; somatic enrichment level: MODERATE (Observed in many cases across multiple studies/cancer contexts.).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:33 O:1
• Conservation: PhyloP100: 0.512
• Publications: 3 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 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 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: 4632.
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000193, AC = 1 — absent/extremely rare (O3 moderate [+2])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=77 | studies=26 | cancer types=18 | level=MODERATE | points=2.0 | reason: Observed in many cases across multiple studies/cancer contexts.

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.1813delA p.Ile605TyrfsTer9	frameshift	Exon 10 of 27	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.1813delA p.Ile605TyrfsTer9	frameshift	Exon 10 of 27	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.1813delA p.Ile605TyrfsTer9	frameshift	Exon 10 of 27	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.1813delAp.Ile605TyrfsTer9

Exon rankExon 10 of 27

frameshift

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.1813delAp.Ile605TyrfsTer9

Exon rankExon 10 of 27

frameshift

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.1813delAp.Ile605TyrfsTer9

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.1813delA p.Ile605TyrfsTer9	frameshift	Exon 10 of 27	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.1813delA p.Ile605TyrfsTer9	frameshift	Exon 10 of 27	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.1444delA p.Ile482TyrfsTer9	frameshift	Exon 10 of 27	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.1813delAp.Ile605TyrfsTer9

Exon rankExon 10 of 27

frameshift

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.1813delAp.Ile605TyrfsTer9

Exon rankExon 10 of 27

frameshift

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.1444delAp.Ile482TyrfsTer9

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000660	AC:1	Hom:0	AN:151588	Cov:32
GnomAD2 exomes	AF: 0.0000345	AC:8	Hom:	AN:232106	Cov:
GnomAD4 exome Warning	AF: 0.00000966	AC:14	Hom:0	AN:1449662	Cov:35
GnomAD4 genome	AF: 0.00000660	AC:1	Hom:0	AN:151588	Cov:32
Local & regional cohorts 1 source Population-specific and national genomic databases
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000223	AC:2	Hom:0	AN:8960	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00000891	1	112186	0.00000531	1	188492

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (10)
8	-	-	not provided (8)
7	-	-	Hereditary breast ovarian cancer syndrome (7)
3	-	-	Familial cancer of breast (3)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	Gastric cancer (1)
-	-	-	Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	0.51

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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: rs80359306;

hg19: chr13-32907420;

COSMIC: COSV66449038;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar