13-32363210-TCG-CTC

Variant names:

• chr13-32363210-TCG-CTC
• NM_000059.4:c.8008_8010delTCGinsCTC
• 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). PS1_Very_StrongPM2PM5

The NM_000059.4(BRCA2):c.8008_8010delTCGinsCTC (p.Ser2670Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.50). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50
• Publications: 0 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
	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).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (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.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)

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.8008_8010delTCGinsCTC p.Ser2670Leu	missense	N/A	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.8008_8010delTCGinsCTC p.Ser2670Leu	missense	N/A	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.8008_8010delTCGinsCTC p.Ser2670Leu	missense	N/A	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.8008_8010delTCGinsCTCp.Ser2670Leu

Exon rankN/A

missense

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.8008_8010delTCGinsCTCp.Ser2670Leu

Exon rankN/A

missense

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.8008_8010delTCGinsCTCp.Ser2670Leu

Exon rankN/A

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.8008_8010delTCGinsCTC p.Ser2670Leu	missense	N/A	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.8008_8010delTCGinsCTC p.Ser2670Leu	missense	N/A	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.7639_7641delTCGinsCTC p.Ser2547Leu	missense	N/A	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.8008_8010delTCGinsCTCp.Ser2670Leu

Exon rankN/A

missense

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.8008_8010delTCGinsCTCp.Ser2670Leu

Exon rankN/A

missense

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.7639_7641delTCGinsCTCp.Ser2547Leu

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	7.5

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr13-32937347;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar