NM_000059.4:c.9477C>A

Variant names:

• chr13-32394909-C-A
• rs80359221
• NM_000059.4:c.9477C>A
• BRCA2 p.Phe3159Leu

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 (ACGS-UK Somatic Oncogenicity v2025). O3_Supporting

The NM_000059.4(BRCA2):c.9477C>A (p.Phe3159Leu) 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 0.00000248 (AC=4) in the gnomAD database across 1,613,916 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.F3159C: Uncertain_significance (ClinVar VariationId 1767080, 1 star); p.F3159= (synonymous): Likely_benign (ClinVar VariationId 4215819, 1 star); p.F3159S: Uncertain_significance (ClinVar VariationId 1171047, 2 stars); p.F3159Y: Uncertain_significance (ClinVar VariationId 1004353, 1 star)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 1.56
• Publications: 10 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: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000015 — very rare (O3 supporting [+1])

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.9477C>A p.Phe3159Leu	missense	Exon 25 of 27	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.9477C>A p.Phe3159Leu	missense	Exon 25 of 27	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.9426C>A p.Phe3142Leu	missense	Exon 25 of 27	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.9477C>Ap.Phe3159Leu

Exon rankExon 25 of 27

missense

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.9477C>Ap.Phe3159Leu

Exon rankExon 25 of 27

missense

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.9426C>Ap.Phe3142Leu

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.9477C>A p.Phe3159Leu	missense	Exon 25 of 27	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.9477C>A p.Phe3159Leu	missense	Exon 25 of 27	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.9108C>A p.Phe3036Leu	missense	Exon 25 of 27	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.9477C>Ap.Phe3159Leu

Exon rankExon 25 of 27

missense

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.9477C>Ap.Phe3159Leu

Exon rankExon 25 of 27

missense

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.9108C>Ap.Phe3036Leu

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152168	Cov:33
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251178	Cov:
GnomAD4 exome	AF: 0.00000205	AC:3	Hom:0	AN:1461748	Cov:31
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152168	Cov:33
TOPMed (Bravo)	AF: 0.0000113	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000445	AC:1	Hom:0	AN:22458	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
GenomeAsia100K	AF: 0.000577	AC:2	Hom:	AN:3478	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41956	0.0000150	1	66886

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

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Breast-ovarian cancer, familial, susceptibility to, 2 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.82	D
FuncVEP CTI	Benign	0.051
GPN-Star LLR	N/A	-3.0
GPN-Star score	N/A	3.0
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.40	T
Mutation Taster	N/A	76/23	polymorphism
PhyloP100	Benign	1.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.021	D
Sift4G	Benign	0.089	T
VESM-3B	Benign	-5.0

Showing 23 of 23 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
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 normal (RUO)

1 no calibration

2 assays found for this variant.

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

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 15–26 in humanized mouse embryonic stem cells

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

• Gene: BRCA2
• Score: -0.492

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.

BS3 supportingFunctionally normalRUO ExCALIBR calibration: BS3 Supporting (-1)

+1 more calibration

BS3 supportingFunctionally normalRUO ExCALIBR calibration (ClinVar 2018): BS3 Supporting (-1)

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: 0.0525

No calibration data

This score is at approximately the 37th 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: rs80359221;

hg19: chr13-32969046;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar