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BRCA1
Final classification
Uncertain Significance
BP1
BRCA1
c.3260G>C
p.Gly1087Ala
missense · exon 10
Gene context NCBI Gene ↗ OncoKB ↗

BRCA1 encodes a large nuclear protein that helps maintain genomic stability by coordinating the repair of DNA double-strand breaks through homologous recombination, and it also regulates transcription and the cell cycle. It acts as a tumor suppressor, working with proteins such as RAD51, BRCA2, BARD1, and PALB2 to preserve genome integrity. Inherited alterations in BRCA1 cause hereditary breast and ovarian cancer syndrome, with elevated risks of breast, ovarian, prostate, and pancreatic cancers, and biallelic loss underlies a rare form of Fanconi anemia. Because BRCA1-driven tumors rely on impaired DNA repair, they are treatable with PARP inhibitors.

This variant

BRCA1 pathogenic variants confer hereditary breast and ovarian cancer risk, but this missense change (p.Gly1087Ala) is classified as Uncertain Significance, meaning current evidence cannot establish whether it disrupts the gene's DNA-repair function. It lies outside all clinically important functional domains and is extremely rare in the general population, so it does not carry the established cancer-risk implications of a confirmed pathogenic BRCA1 alteration.

Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.3260G>C
GRCh38
chr17:43092271 C>G
GRCh37
chr17:41244288 C>G
Basis Uncertain Significance: only BP1 (Strong benign) is met, and a single benign code does not satisfy the ENIGMA Likely Benign combination rule, which requires multiple independent evidence types. ▾
Uncertain Significance: only BP1 (Strong benign) is met, and a single benign code does not satisfy the ENIGMA Likely Benign combination rule, which requires multiple independent evidence types.
Classification rationale
BP1 Uncertain Significance
BRCA1 c.3260G>C missense · exon 10

BP1 (Strong): missense change outside all ENIGMA-defined BRCA1 functional domains with no predicted splicing impact (SpliceAI max delta 0.01, threshold <=0.1). Overall classification: Uncertain Significance — the single BP1 Strong benign code does not satisfy any ENIGMA Table 3 Likely Benign combination, which requires multiple independent benign evidence types.

BP1 → Uncertain Significance
Gene diagram · NM_007294.4 · variants mapped to exon structure
BRCA1 NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 14 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 · 1
Strength Supporting Moderate Strong Very strong
✓
BP1 strong Benign
Met (Strong): p.Gly1087Ala lies outside all ENIGMA-defined BRCA1 domains, with SpliceAI max delta 0.01 (below the 0.1 threshold).
ENIGMA BRCA1/2 v1.2 BP1 rule: 'Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI<=0.1).' Domains defined as BRCA1 RING aa 2-101; coiled-coil aa 1391-1424; BRCT repeats aa 1650-1857.Residue 1087 lies outside all three defined domain intervals.SpliceAI lookup evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).' (DS_AG=0.0 and other component scores similarly low), satisfying the SpliceAI<=0.1 no-splicing-predicted condition.
cspec ↗spliceai ↗
Assessed · not applied · 4 not met · 10 not assessed
Pathogenic
PS1 Not assessed: no comparator variant producing the same p.Gly1087Ala change through a different nucleotide substitution was identified.
PS3 Not assessed: no calibrated functional assay result for p.Gly1087Ala has been published in any VCEP-curated dataset.
PS4 Not assessed: no case-control counts, p-value, odds ratio, or confidence interval for this variant were available.
PM2 Not met: the variant is present in gnomAD v2.1 controls (1/250,540 alleles), failing the required absence from controls.
PM3 Not assessed: no Fanconi anemia phenotype, second BRCA1 variant, or phase information was documented.
PP1 Not assessed: no family pedigree, parental testing, or segregation data were available for this variant.
PP3 Not met: SpliceAI max delta 0.015 is below the 0.2 threshold, and the BayesDel pathway applies only within functional domains.
PP4 Not assessed: no calibrated multifactorial likelihood ratio for this variant was available.
Benign
BA1 Not met: gnomAD v2.1 allele frequency 3.99e-06 is far below the 0.1% BA1 threshold.
BS1 Not met: gnomAD grpmax FAF 1.57e-05 does not reach the BS1 supporting threshold of 2e-05.
BS2 Not assessed: no qualifying unaffected-individual observations were available to evaluate BS2.
BS3 Not assessed: no calibrated functional assay evidence supporting a benign effect on p.Gly1087Ala was available.
BS4 Not assessed: no family or segregation data were available to evaluate lack of segregation.
BP5 Not assessed: no calibrated multifactorial likelihood ratio against pathogenicity was available.
N/A · 13 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.79719e-05; MAF= 0.00180%, 29/1613632 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.28814e-05; MAF= 0.00229%, 27/1179998 alleles, homozygotes = 0); grpmax FAF= 1.567e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.99138e-06; MAF= 0.00040%, 1/250540 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15309e-05; MAF= 0.00615%, 1/16252 alleles, homozygotes = 0).
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0018% · 29 / 1,613,632
0 hom · FAF 0.0016%
European (non-Finnish)
27 / 1,179,998
0.0023%
Remaining individuals
1 / 62,482
0.0016%
African/African American
1 / 74,866
0.0013%
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0004% · 1 / 250,540
0 hom
African/African American
1 / 16,252
0.0062%
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 54812)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.374. BayesDel score = -0.184442.
SpliceAI ↗
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99066382, n = 1 times).
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 · 8 PMIDs not cited in assessment
15385441 ↗ Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. CLINVAR
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR
31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". CLINVAR
17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR
23188549 ↗ NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. CLINVAR
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
26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR