chr13-32357830-G-A

Variant names:

• chr13-32357830-G-A
• rs587781943
• NM_000059.4:c.7706G>A
• BRCA2 p.Gly2569Asp

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2_Supporting

The NM_000059.4(BRCA2):c.7706G>A (p.Gly2569Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,624 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000655. 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 Uncertain Significance (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G2569A: Uncertain_significance (ClinVar VariationId 4802345, 1 star); p.G2569C: Uncertain_significance (ClinVar VariationId 1760231, 1 star); p.G2569S: Uncertain_significance (ClinVar VariationId 441356, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 4.58
• 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 ACMG Germline Pathogenicity v2019

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: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000655 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000139 by highest known P/LP ClinVar AF 0.000139) — PM2 supporting.

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.7706G>A p.Gly2569Asp	missense	Exon 16 of 27	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.7706G>A p.Gly2569Asp	missense	Exon 16 of 27	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.7706G>A p.Gly2569Asp	missense	Exon 16 of 27	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.7706G>Ap.Gly2569Asp

Exon rankExon 16 of 27

missense

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.7706G>Ap.Gly2569Asp

Exon rankExon 16 of 27

missense

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.7706G>Ap.Gly2569Asp

Exon rankExon 16 of 27

missense

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.7706G>A p.Gly2569Asp	missense	Exon 16 of 27	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.7706G>A p.Gly2569Asp	missense	Exon 16 of 27	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.7337G>A p.Gly2446Asp	missense	Exon 16 of 27	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.7706G>Ap.Gly2569Asp

Exon rankExon 16 of 27

missense

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.7706G>Ap.Gly2569Asp

Exon rankExon 16 of 27

missense

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.7337G>Ap.Gly2446Asp

Exon rankExon 16 of 27

missense

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152148	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251340	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461624	Cov:31
GnomAD4 genome Warning	AF: 0.00000657	AC:1	Hom:0	AN:152148	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:36930	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
Korea4K (4,157 Koreans)	AF: 0.000276	AC:2	Hom:	AN:7232	Cov:

Showing 7 sources

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary breast ovarian cancer syndrome (2)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	2	-	not provided (2)
-	1	-	BRCA2-related cancer predisposition (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.90	D
FuncVEP CTI	Benign	0.084
GPN-Star LLR	N/A	-3.1
GPN-Star score	N/A	3.1
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.062	D
Mutation Taster	N/A	93/7	polymorphism
PhyloP100	Uncertain	4.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.047	D
VESM-3B	Benign	-6.7

Showing 23 of 23 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.020	Details are displayed if max score is > 0.2

Showing 2 of 2 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.

1 no calibration

1 assay found for this variant.

No calibration: 1 assay (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Nucleotide level

Scores from sGE of BRCA2 exons 15 to 26 in Hap1 cells

SGE of BRCA2 exons 15 to 26 in Hap1 cells

• Gene: BRCA2
• Score: 0.243

No calibration data

This score is at approximately the 91th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs587781943;

hg19: chr13-32931967;

COSMIC: COSV109719300;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar