GeneBe

NM_000059.4:c.6267_6269delGCAinsC

Variant names:
GermlineCancer

Variant summary

Our verdict is Pathogenic.
>+14 Pathogenic
-7
-6
-1
0
+5
+6
+9
+10
B
LB
VUS
LP
P
 The variant received 18 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.6267_6269delGCAinsC (p.Glu2089AspfsTer2) variant causes a frameshift, missense change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★).

Frequency

Genomes: not found (cov: 33)

Consequence

BRCA2
NM_000059.4 frameshift, missense

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:17

Conservation

PhyloP100: -0.180

Publications

5 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

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000059.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 18 points.

PVS1Null variant in LOF gene
Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 11 of 27) at amino acid 2089 of 3418, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~2089 amino acids (1329 amino acids lost).
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.
PP5Reputable source reports pathogenic
ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (17/17 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

BRCA2 NM_000059.4
MANE Select
HGVSc / HGVSpc.6267_6269delGCAinsCp.Glu2089AspfsTer2
Exon rankExon 11 of 27
frameshiftmissense
Prot: NP_000050.3UniProt: A0A7P0T9D7P51587
BRCA2 NM_001432077.1
HGVSc / HGVSpc.6267_6269delGCAinsCp.Glu2089AspfsTer2
Exon rankExon 11 of 27
frameshiftmissense
Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587
BRCA2 NM_001406720.1
HGVSc / HGVSpc.6267_6269delGCAinsCp.Glu2089AspfsTer2
Exon rankExon 11 of 27
frameshiftmissense
Prot: NP_001393649.1UniProt: A0A8V8TPZ2

Ensembl Transcripts

BRCA2 ENST00000380152.8
TSL:5MANE Select
HGVSc / HGVSpc.6267_6269delGCAinsCp.Glu2089AspfsTer2
Exon rankExon 11 of 27
frameshiftmissense
Prot: ENSP00000369497.3UniProt: P51587
BRCA2 ENST00000544455.6
TSL:1
HGVSc / HGVSpc.6267_6269delGCAinsCp.Glu2089AspfsTer2
Exon rankExon 11 of 27
frameshiftmissense
Prot: ENSP00000439902.1UniProt: P51587
BRCA2 ENST00000530893.7
TSL:1
HGVSc / HGVSpc.5898_5900delGCAinsCp.Glu1966AspfsTer2
Exon rankExon 11 of 27
frameshiftmissense
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)
Global population databases 2 sources
GnomAD3 genomes
Cov:33
GnomAD4 genome
Cov:33
Showing 2 sources

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
7
-
-
Breast-ovarian cancer, familial, susceptibility to, 2 (7)
3
-
-
Hereditary breast ovarian cancer syndrome (3)
2
-
-
Hereditary cancer-predisposing syndrome (2)
2
-
-
not provided (2)
1
-
-
BRCA2-related disorder (1)
1
-
-
Familial cancer of breast (1)
1
-
-
Ovarian neoplasm (1)

Computational Scores

Mutation Taster
N/A0/200disease causing (fs/PTC)
PhyloP100
Benign-0.18
Showing 2 of 2 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.

No MaveDB functional evidence found for this variant.

Publications

Other links and lift over

dbSNP: rs276174868;
hg19: chr13-32914759;
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.