chr13-32394717-C-G

Variant names:

• chr13-32394717-C-G
• rs80359198
• NM_000059.4:c.9285C>G
• BRCA2 p.Asp3095Glu

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_StrongO3_ModerateO5_ModerateO6_Supporting

The NM_000059.4(BRCA2):c.9285C>G (p.Asp3095Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.00000137 (AC=2) in the gnomAD database across 1,461,362 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000073792: Experimental studies have shown that this missense change affects BRCA2 function (PMID:18451181, 22678057, 23108138)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.D3095G: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 409512) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D3095A: Uncertain_significance (ClinVar VariationId 1330142, 1 star); p.D3095= (synonymous): Likely_benign (ClinVar VariationId 184910, 3 stars) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 1.46
• Publications: 2 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: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		CGI exact DNA-change oncogenic — Strong (O1); TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (4.0 pts): CGI (Cancer Genome Interpreter), ClinVar germline P/LP in TSG (★★)
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000000, AC = 2 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Same AA change as established oncogenic variant (or germline P/LP in TSG) — Moderate (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: true | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect

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.9285C>G p.Asp3095Glu	missense	Exon 25 of 27	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.9285C>G p.Asp3095Glu	missense	Exon 25 of 27	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.9234C>G p.Asp3078Glu	missense	Exon 25 of 27	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.9285C>Gp.Asp3095Glu

Exon rankExon 25 of 27

missense

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.9285C>Gp.Asp3095Glu

Exon rankExon 25 of 27

missense

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.9234C>Gp.Asp3078Glu

Exon rankExon 25 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.9285C>G p.Asp3095Glu	missense	Exon 25 of 27	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.9285C>G p.Asp3095Glu	missense	Exon 25 of 27	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.8916C>G p.Asp2972Glu	missense	Exon 25 of 27	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.9285C>Gp.Asp3095Glu

Exon rankExon 25 of 27

missense

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.9285C>Gp.Asp3095Glu

Exon rankExon 25 of 27

missense

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.8916C>Gp.Asp2972Glu

Exon rankExon 25 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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.00000399	AC:1	Hom:	AN:250672	Cov:
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1461362	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Hereditary breast ovarian cancer syndrome (5)
3	-	-	Hereditary cancer-predisposing syndrome (3)
3	-	-	not provided (3)
1	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (2)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	Familial cancer of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	0.19
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.78	D
FuncVEP CTI	Pathogenic	0.59
GPN-Star LLR	N/A	-4.4
GPN-Star score	N/A	4.4
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.66	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
PhyloP100	Benign	1.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.023	D
VESM-3B	Benign	-11

Showing 23 of 23 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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 abnormal

1 abnormal (RUO)

1 no calibration

3 assays found for this variant.

Clinical calibration: 1 functionally abnormal (PS3), 0 functionally normal (BS3).

Research-use-only (RUO) calibration: 1 functionally abnormal (PS3), 0 functionally normal (BS3).

No calibration: 1 assay (score only).

RUO results are not validated; give them no weight next to the clinical ones.

Nucleotide level

Scores from arrayed screen of BRCA2 homology directed repair function in VC-8 cells

Arrayed screen of BRCA2 homology directed repair function in VC-8 cells

• Gene: BRCA2
• Assay type: Reporter
• Mechanism: DNA repair and Double-strand break repair via homologous recombination
• Model system: Other (Cricetulus griseus)
• Score: 0.948 · p.Asp3095Glu (assay numbering)

Classified as

PS3 strongFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Functionally abnormal

+3 more calibrations

PS3 strongFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Functionally abnormal

PS3 very strongFunctionally abnormalRUO ExCALIBR calibration: PS3 Very Strong (8)

PS3 very strongFunctionally abnormalRUO ExCALIBR calibration (ClinVar 2018): PS3 Very Strong (8)

Nucleotide level

Scores from sGE of BRCA2 exons 15–26 in humanized mouse embryonic stem cells

SGE of BRCA2 exons 15–26 in humanized mouse embryonic stem cells

• Gene: BRCA2
• Score: -3.76

Classified as

No clinical calibration. Only research-use-only (RUO) calibrations exist for this assay — they are not reliable evidence; treat them with extreme caution.

PS3 moderate plusFunctionally abnormalRUO ExCALIBR calibration: PS3 Moderate+ (3)

+1 more calibration

PS3 moderate plusFunctionally abnormalRUO ExCALIBR calibration (ClinVar 2018): PS3 Moderate+ (3)

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: -0.878

No calibration data

This score is at approximately the 6th 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: rs80359198;

hg19: chr13-32968854;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar