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 ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 11 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PVS1 very strong review Pathogenic

This variant is a frameshift deletion in BRCA1 exon 10 (legacy exon 11) predicted to cause p.(Thr688LysfsTer13). Under the ENIGMA BRCA1 specification, truncating variants in this exon meet PVS1, consistent with BRCA1 loss of function as an established disease mechanism.

NM_007294.4:c.2063del normalizes to p.(Thr688LysfsTer13) / p.(T688Kfs*13)Variant maps to BRCA1 exon 10ENIGMA Table 4 assigns exon 10(11) truncating variants to PVS1

cspec ↗

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the ENIGMA BRCA1 PM2 threshold for absence from population controls.

Absent from gnomAD v2.1Absent from gnomAD v4.1

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PM5 strong review Pathogenic

This protein-truncating variant occurs in BRCA1 exon 10 (legacy exon 11), an exon designated PM5_Strong (PTC) in the ENIGMA BRCA1 exon table, indicating that different proven pathogenic protein-truncating variants have been observed in this exon.

Variant is a protein-truncating frameshiftENIGMA Table 4 assigns exon 10(11) PM5_Strong (PTC)

cspec ↗

Assessed · not applied · 2 not met · 9 not assessed

Pathogenic

PS3 No variant-specific calibrated functional study result was identified for this frameshift variant in the curated ENIGMA functional assay resources, so PS3 was not applied.

PS4 No case-control study or quantified enrichment data were identified for this exact variant, so PS4 cannot be applied.

PM3 No data were identified showing this variant in trans with another BRCA1 variant in an individual with BRCA1-related Fanconi anemia, so PM3 was not applied.

PP1 No segregation data were identified for this variant, so PP1 was not applied.

PP4 No variant-level clinical-history likelihood ratio entry was identified for this exact variant in the BRCA1 ENIGMA clinical-history resource, so PP4 was not applied.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the BA1 population threshold.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the BS1 population frequency thresholds.

BS2 No qualifying observations in individuals lacking features of BRCA1-related Fanconi anemia were identified for this variant, so BS2 was not applied.

BS3 No variant-specific calibrated functional study showing no damaging effect was identified for this frameshift variant in the curated ENIGMA functional assay resources, so BS3 was not applied.

BS4 No non-segregation data were identified for this variant, so BS4 was not applied.

BP5 No variant-level clinical-history likelihood ratio entry was identified for this exact variant in the BRCA1 ENIGMA clinical-history resource, so BP5 was not applied.

N/A · 14 PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

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

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