NM_000059.4:c.8009C>T

Variant names:

• chr13-32363211-C-T
• rs80359035
• NM_000059.4:c.8009C>T
• BRCA2 p.Ser2670Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS3PM5PP3_ModeratePP5_Strong

The NM_000059.4(BRCA2):c.8009C>T (p.Ser2670Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000248 (AC=4) in the gnomAD database across 1,613,428 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000208. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.50). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000073398: Experimental studies have shown that this missense change affects BRCA2 function (PMID:19043619, 29394989, 32444794)." 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.S2670W: Pathogenic (ClinVar VariationId 489785, 3 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S2670P: Uncertain_significance (ClinVar VariationId 1001575, 2 stars); p.S2670= (synonymous): Likely_benign (ClinVar VariationId 183837, 3 stars) 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22 U:1 O:1
• Conservation: PhyloP100: 7.50
• 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 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 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000073398: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 19043619, 29394989, 32444794).; SCV001426773: "The most pronounced variant effect results in loss of homology directed DNA repair (HDR) capability (Hart_2019, Guidugli_2018, Karchin_2008)."; SCV001478293: In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.99 and an overall classification of pathogenic. (PS3_strong).; SCV000186012: "This variant was found to be functionally defective in a homology-directed repair assay (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Hart SN et al. Genet. Med., 2019 01;21:71-80)."; SCV000683935: Functional studies reported this variant results in the production of BRCA2 protein that is severely impaired in homology-directed repair assays (PMID: 19043619, 29394989). An RNA study found the variant resulted in splicing defects predicted to cause an absent or non-functional protein product (PMID: 31843900).; SCV000210458: Published functional studies demonstrate a damaging effect: impaired homology directed repair activity and sensitivity to PARP inhibitors (PMID: 29394989, 29884841, 32444794).; SCV000889147: Experimental studies indicate that this variant has a damaging effect on the expression and function of the BRCA2 protein in vitro (PMID: 31843900 (2019), 29394989 (2018), 28339459 (2017), 19043619 (2008)).; SCV000592170: Through a homology-directed DNA repair assay, the p.Ser2670Leu variant was found to substantially decrease HDR compared to wild-type BRCA2 and known neutral variants, and was predicted to be deleterious (Guidugli_2017_PMID:29394989).; SCV005346982: "studies using a homology directed DNA repair activity assay showed this variant is functionally defective" (Hart et al. 2018. PubMed ID: 29884841; Guidugli et al. 2012. PubMed ID: 23108138).
	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.S2670W: Pathogenic (ClinVar VariationId 489785, 3 stars); Other variants at the same amino acid residue (not pathogenic): p.S2670P: Uncertain_significance (ClinVar VariationId 1001575, 2 stars); p.S2670= (synonymous): Likely_benign (ClinVar VariationId 183837, 3 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	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 (22/23 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.8009C>T p.Ser2670Leu	missense	Exon 18 of 27	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.8009C>T p.Ser2670Leu	missense	Exon 18 of 27	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.8009C>T p.Ser2670Leu	missense	Exon 18 of 27	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.8009C>Tp.Ser2670Leu

Exon rankExon 18 of 27

missense

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.8009C>Tp.Ser2670Leu

Exon rankExon 18 of 27

missense

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.8009C>Tp.Ser2670Leu

Exon rankExon 18 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.8009C>T p.Ser2670Leu	missense	Exon 18 of 27	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.8009C>T p.Ser2670Leu	missense	Exon 18 of 27	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.7640C>T p.Ser2547Leu	missense	Exon 18 of 27	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.8009C>Tp.Ser2670Leu

Exon rankExon 18 of 27

missense

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.8009C>Tp.Ser2670Leu

Exon rankExon 18 of 27

missense

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.7640C>Tp.Ser2547Leu

Exon rankExon 18 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: 0.0000132	AC:2	Hom:0	AN:151936	Cov:32
GnomAD4 exome Warning	AF: 0.00000137	AC:2	Hom:0	AN:1461492	Cov:31
GnomAD4 genome	AF: 0.0000132	AC:2	Hom:0	AN:151936	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:200630	Cov:

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000172	1	58190	0.00	0	80498

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

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (5)
4	-	-	Hereditary breast ovarian cancer syndrome (4)
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	BRCA2-related disorder (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 (1)
1	-	-	Malignant tumor of breast (1)
1	-	-	Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	27
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.83
GPN-Star LLR	N/A	-5.9
GPN-Star score	N/A	5.9
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.73	D
Mutation Taster	N/A	25/75	disease causing (ClinVar)
PhyloP100	Uncertain	7.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
VESM-3B	Benign	-11

Showing 25 of 25 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2
Splicevardb	N/A	3.0

Showing 3 of 3 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 assay found for this variant.

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

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: 0.976 · p.Ser2670Leu (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)

Other links and lift over

dbSNP: rs80359035;

hg19: chr13-32937348;

COSMIC: COSV66453386;

COSMIC: COSV66453386;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar