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NM_007294.4:c.3260G>C
p.Gly1087Ala · BRCA1
ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.2 · v1.2
0%
complete
Final classification
VUS
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 maintains genomic stability by repairing DNA double-strand breaks, and inherited pathogenic changes in it raise the risks of hereditary breast, ovarian, prostate, and pancreatic cancers. This p.Gly1087Ala change is a variant of uncertain significance: current evidence (very low population frequency, location outside the protein's key functional domains, no predicted splicing effect) is insufficient to determine whether it impairs BRCA1's tumor-suppressor function and cancer risk.

Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.3260G>C
GRCh38
chr17:43092271 C>G
GRCh37
chr17:41244288 C>G
Final classification: VUS under the ClinGen ENIGMA BRCA1/2 Expert Panel Specification v1.2. Only BP1 is met (Strong, benign): p.Gly1087Ala is a missense change outside all ENIGMA clinically important BRCA1 domains, with SpliceAI max delta 0.015 below 0.1. One strong-benign criterion reaches neither Benign (BA1 or >=2 Strong) nor Likely Benign (1 Strong plus additional evidence), no pathogenic criteria are met, and the variant therefore defaults to Uncertain Significance. Flagged for human review: if the disputed BS1 frequency record (current gnomAD grpmax FAF 1.567e-05 vs historical MAF 6.7e-05) were upheld as supporting, BP1_Strong plus BS1 would reach Likely Benign.
Classification rationale
BP1 VUS
BRCA1 c.3260G>C missense · exon 10

BP1 (Strong): p.Gly1087Ala is a missense change outside all ENIGMA clinically important BRCA1 domains (RING, coiled-coil, BRCT), with SpliceAI max delta 0.015 below the 0.1 threshold. Overall classification: VUS - the lone BP1_Strong meets neither the ENIGMA Benign rule (BA1 or >=2 Strong) nor the Likely Benign rule (1 Strong plus additional evidence), so the variant defaults to Uncertain Significance.

BP1 → VUS
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 · 1 applied · 17 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 is a missense change outside all ENIGMA clinically important BRCA1 domains, with SpliceAI max delta 0.015 below the 0.1 threshold.
The case variant is NM_007294.4:c.3260G>C, p.(Gly1087Ala), a missense substitution at residue 1087.The governing ENIGMA domain definitions are BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 1087 is outside every listed domain.SpliceAI reports DS_AG 0.0, DS_AL 0.015, DS_DG 0.001, and DS_DL 0.001, with maximum delta 0.015; this is below the ENIGMA BP1 threshold of 0.1.
cspec ↗spliceai ↗
Assessed · not applied · 8 not met · 9 not assessed
Pathogenic
PVS1 Not met: p.(Gly1087Ala) is a missense substitution with an unchanged predicted protein endpoint, not a null variant.
PS1 Not assessed: no documented pathogenic BRCA1 variant producing the same amino-acid change was available for comparison.
PS3 Not assessed: no calibrated functional assay or published study of this exact variant was available.
PS4 Not assessed: no case-control data for this exact variant were available.
PM2 Not met: the variant is observed in population controls (gnomAD v2.1: 1/250,540 alleles), where PM2 requires absence.
PM3 Not assessed: no patient phenotype, second BRCA1 variant, or phase data were available to evaluate a Fanconi anemia presentation.
PP1 Not assessed: no quantitative co-segregation data (segregation likelihood ratio or affected-relative genotypes) were available.
PP3 Not met: p.Gly1087Ala lies outside the clinically important BRCA1 domains, and its SpliceAI max delta of 0.015 is below the 0.2 threshold.
PP4 Not met: the combined multifactorial likelihood ratio is 0.31, below the PP4 thresholds.
Benign
BA1 Not met: gnomAD v2.1 allele frequency is 3.99e-06, far below the >0.001 BA1 threshold.
BS1 Not met: current gnomAD v4.1 grpmax FAF is 1.567e-05, below the BS1 supporting threshold of 2e-05.
BS2 Not assessed: no patient-level data (phenotype, chromosome-breakage result, biallelic genotype) were available to assess recessive-disease features.
BS3 Not assessed: no functional studies demonstrating a benign effect of this exact variant were available.
BS4 Not assessed: no quantitative segregation data (non-segregating affected relatives) were available.
BP4 Not met: although BayesDel (-0.18) and SpliceAI (0.015) pass their cutoffs, p.Gly1087Ala lies outside the BRCA1 domains BP4 requires.
BP5 Not met: the combined multifactorial likelihood ratio of 0.31 does not meet the ENIGMA BP5 supporting requirement.
BP7 Not assessed: no variant-specific RNA assay was available, and BP7 otherwise applies only to synonymous or intronic variants.
N/A · 10 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6
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
23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. 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
10923033 ↗ The breast cancer information core: database design, structure, and scope. CLINVAR
20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR