Classification rationale

BP1 Uncertain Significance

BRCA1 c.3271C>G

The BRCA1 c.3271C>G (p.Pro1091Ala; p.P1091A) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, supporting rarity, although the ENIGMA BRCA1 PM2_Supporting rule was not applied because the required specified-control-set and coverage documentation were not identified here.² SpliceAI predicts no significant splice effect (maximum delta score 0.01, below the ENIGMA 0.1 and 0.2 splice thresholds); BayesDel no-AF is -0.072 and REVEL is 0.572, and because p.Pro1091Ala lies outside the BRCA1 RING, coiled-coil, and BRCT domains, the ENIGMA BRCA1 missense rules support BP1_Strong and do not support PP3.³

BP1 → Uncertain Significance

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

3 spliceai ↗bayesdelrevelcspec ↗vcep_appendices_v1_2_2024_11_18

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

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 17 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

BP1 strong Benign

This missense variant occurs at p.Pro1091Ala, outside the BRCA1 clinically important domains defined by ENIGMA (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP1 threshold of 0.1. These findings meet BP1_Strong.

Protein position 1091 is outside the ENIGMA BRCA1 clinically important domains.SpliceAI max delta = 0.01.

cspec ↗spliceai ↗

Assessed · not applied

Pathogenic

PVS1 This is a missense variant, not a nonsense, frameshift, initiation-codon, deletion, or canonical ±1,2 splice variant, so it does not meet the BRCA1 ENIGMA or generic null-variant requirements for PVS1.

PS1 No previously classified pathogenic or likely pathogenic variant with the same amino acid change or the same predicted splicing effect was identified in the reviewed ClinVar or BRCA1 ENIGMA materials, so PS1 was not applied.

PS3 No variant-specific calibrated functional study assigning PS3 was identified for this variant in the reviewed BRCA1 ENIGMA functional tables, and no variant-specific reviewed functional evidence was identified in OncoKB.

PS4 No case-control dataset or other quantitative prevalence evidence showing enrichment of this variant in affected individuals versus controls was identified, so PS4 was not applied.

PM2 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which supports rarity; however, the ENIGMA BRCA1 PM2_Supporting rule specifically requires absence in the specified control datasets together with average read depth ≥25, and the required v3.1/depth documentation was not identified here, so PM2 was not applied.

PM3 No evidence was identified showing this variant in trans with another BRCA1 variant in an individual with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not applied.

PP1 No quantitative co-segregation evidence was identified for this variant, so PP1 was not applied.

PP3 SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the ENIGMA splicing threshold of 0.2 for PP3.

PP4 No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified in the reviewed BRCA1 clinical-history resources, so PP4 was not applied.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the ENIGMA BA1 filter allele frequency threshold of greater than 0.1% (FAF >0.001).

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the ENIGMA BS1 thresholds of greater than 0.002% or greater than 0.01% filter allele frequency.

BS2 No proband-level evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia under the ENIGMA point-based BS2 framework, so BS2 was not applied.

BS3 No variant-specific calibrated functional study assigning BS3 was identified for this variant in the reviewed BRCA1 ENIGMA functional tables, so BS3 was not applied.

BS4 No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not applied.

BP4 SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, and BayesDel no-AF is -0.072, which is below the ENIGMA benign missense threshold of 0.15.

BP5 No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds against pathogenicity was identified in the reviewed BRCA1 clinical-history resources, so BP5 was not applied.

BP7 This is a missense variant.

N/A · 10 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.572. BayesDel score = -0.0721595.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

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

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

Re-run this variant?