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 Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 21 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPS3PM2PM5PP3PP5_Strong

The NM_000059.4(BRCA2):c.9285C>G (p.Asp3095Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 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: Pathogenic. The variant received 21 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000073792: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 22678057, 23108138).; SCV000695233: In these functional studies the variant was shown to cause significantly reduced HDR activity, increased aberrant centriole amplification, and reduced cell viability in null-rescue survival assays (example: Farrugia_2008, Biswas_2012, Guidugli_2012, Hart_2018, Mesman_2018, Ikegami_2020).; SCV001478279: The variant has a probability of pathogenicity of 1.0 (PS3_strong).; SCV006311323: Experimental studies have shown that this missense change affects BRCA2 function (PMID:18451181, 22678057, 23108138).; SCV000276898: A homology-directed DNA repair (HDR) assay has demonstrated this variant to be non-functional (Guidugli L et al. Am J Hum Genet 2018 02;102(2):233-248; Hart SN et al. Genet Med, 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet 2021 03;108(3):458-468).; SCV000684048: Functional studies have shown that this variant disrupts homology-directed DNA repair activity (PMID: 18451181, 23108138, 29884841, 33609447) and fails to complement cell lethality phenotype induced by loss of BRCA2 in mouse embryonic stem cell-based assays (PMID: 24323938, 29988080, 37922907).; SCV000292530: Published functional studies demonstrate a damaging effect: reduced homology-directed repair (HDR) activity, aberrant centriole amplification, failure to rescue lethality of Brca2 null ES cells (Farruguia et al., 2008; Biswas et al., 2012; Guidugli et al., 2013; Ikegami et al., 2020; Richardson et al., 2021); SCV000600853: Published functional studies have shown that this variant results in a deleterious effect on BRCA2 protein function (PMID: 22678057 (2012), 29394989 (2018), 29988080 (2018)).; SCV005425843: Functional studies have shown that this variant disrupts homology-directed DNA repair activity (PMID: 18451181, 23108138, 29884841) and fails to complement cell lethality phenotype induced by loss of BRCA2 in mouse embryonic stem cell-based assays (PMID: 24323938, 29988080).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000003 — very rare for AD+AR gene (base 0.0001, raised to 0.000139 by highest known P/LP ClinVar AF 0.000139) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.D3095G: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 409512); Other variants at the same amino acid residue (not pathogenic): p.D3095A: Uncertain_significance (ClinVar VariationId 1330142, 1 star); p.D3095= (synonymous): Likely_benign (ClinVar VariationId 184910, 3 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (14/15 total P/LP).

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