Starting

Initialising…

BRCA1

Final classification

Pathogenic

BRCA1 c.2063del · p.Thr688LysfsTer13

BRCA1

The BRCA1 c.2063del (p.Thr688LysfsTer13; p.T688Kfs*13) variant has not been observed in COSMIC and has not been reported in ClinVar.

Gene

BRCA1

Transcript

NM_007294.4

HGVS · transcript:coding

NM_007294.4:c.2063del

Consequence

N/A

GRCh38

chr17:43093467 TG>T

GRCh37

chr17:41245484 TG>T

Basis ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework via CSPEC/VCEP override for final criteria combinations. ▾

ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework via CSPEC/VCEP override for final criteria combinations.

Classification rationale

PVS1PM2PM5 Pathogenic

BRCA1 c.2063del

The BRCA1 c.2063del (p.Thr688LysfsTer13; p.T688Kfs*13) variant has not been observed in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.² This frameshift deletion occurs in BRCA1 exon 10 (legacy exon 11) and is predicted to introduce a premature termination codon; under the ENIGMA BRCA1 specification, truncating variants in this exon meet PVS1 and the exon also carries PM5_Strong (PTC).³ SpliceAI predicts no significant additional splice impact for this deletion, with a maximum delta score of 0.00.⁴

PVS1 + PM2 + PM5 → Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗vcep_specifications_table4_v1_2_2024_11_18pvs1_variant_assessment

4 spliceai ↗

Gene diagram · NM_007294.4 · variants mapped to exon structure

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

11358863 ↗ Tumorigenesis in mice carrying a truncating Brca1 mutation. ONCOKB

12483515 ↗ The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans. ONCOKB

12947386 ↗ Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. ONCOKB

20608970 ↗ BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications. ONCOKB

20104584 ↗ Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. CLINVAR

23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. CLINVAR

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR