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NM_007294.4:c.2501G>A
p.Gly834Glu · 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
Likely Benign
BS1BP1
BRCA1
c.2501G>A
p.Gly834Glu
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

Pathogenic BRCA1 variants cause hereditary breast and ovarian cancer syndrome by disabling a tumor suppressor that repairs DNA double-strand breaks. This Likely Benign classification indicates c.2501G>A is not expected to impair that function: it alters residue 834 outside BRCA1's clinically important domains and shows no predicted splicing effect. On this basis the variant should not be used to assign the elevated breast, ovarian, prostate, or pancreatic cancer risks that accompany pathogenic BRCA1 alterations.

Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.2501G>A
GRCh38
chr17:43093030 C>T
GRCh37
chr17:41245047 C>T
Likely Benign: BP1_Strong (-4 points) plus BS1_Supporting (-1 point) totals -5, within the ENIGMA -6 to -2 Likely Benign range.
Classification rationale
BS1BP1 Likely Benign
BRCA1 c.2501G>A missense · exon 10

BP1 (Strong): missense p.(Gly834Glu) at residue 834, outside all clinically important BRCA1 domains (RING, coiled-coil, BRCT), with no predicted splice impact (SpliceAI max delta 0.001). BS1 (Supporting): gnomAD v4.1 group-maximum FAF 5.137e-05 falls in the supporting frequency range (>0.00002 to <=0.0001). Likely Benign: one Strong (-4) plus one Supporting (-1) benign criterion totals -5 ENIGMA points, within the -6 to -2 range.

BS1 + BP1 → Likely Benign
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 · 2 applied · 16 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 · 2
Strength Supporting Moderate Strong Very strong
BS1 supporting Benign
Met (Supporting): the gnomAD v4.1 group-maximum FAF of 5.137e-05 falls in the supporting range (>0.00002 to <=0.0001).
The ENIGMA BRCA1 and BRCA2 specification v1.2 defines BS1_Supporting as FAF >0.00002 and <=0.0001 in gnomAD v2.1 and/or gnomAD v3.1 non-cancer, non-founder populations.gnomAD v4.1 reports group-maximum FAF 5.137e-05 and highest observed South Asian AF 9.88121e-05, placing the group-maximum FAF within the ENIGMA BS1_Supporting interval.gnomAD v2.1 reports group-maximum FAF 1.082e-05, total AF 7.96724e-06, and zero homozygotes; this does not independently reach the BS1_Supporting lower threshold.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP1 strong Benign
Met (Strong): residue 834 lies outside every clinically important BRCA1 domain (RING, coiled-coil, BRCT), with SpliceAI max delta 0.001.
ENIGMA BRCA1/2 specification v1.2 defines BP1_Strong for missense or in-frame variants outside a clinically important functional domain when no splicing is predicted (SpliceAI ≤0.1).The same specification defines BRCA1 clinically important functional domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Gly834 is outside every listed domain.The case variant is NP_009225.1:p.(Gly834Glu), and SpliceAI reports max_delta_score 0.001, satisfying the no-significant-splice-impact condition.
cspec ↗spliceai ↗
Assessed · not applied · 5 not met · 11 not assessed
Pathogenic
PVS1 Not met: p.(Gly834Glu) is a missense change with no predicted premature termination or nonsense-mediated decay, and SpliceAI max delta is only 0.001.
PS1 Not assessed: no pathogenic or likely pathogenic comparator with the same amino-acid change (p.Gly834Glu) was identified.
PS3 Not assessed: no calibrated functional assay result for p.(Gly834Glu) meeting the specification's Table 9 requirement was available.
PS4 Not assessed: the two cohort observations provide no matched case-control comparison meeting the required p<=0.05 and OR>=4.
PM2 Not met: the variant is present in population databases (2 alleles in gnomAD v2.1, 11 in gnomAD v4.1) rather than absent from controls.
PM3 Not assessed: no Fanconi anemia phenotype or co-occurring pathogenic BRCA1 variant in the same gene was documented.
PP1 Not assessed: no affected-relative genotypes or quantitative co-segregation data were available.
PP3 Not met: residue 834 lies outside the clinically important RING, coiled-coil, and BRCT domains, and SpliceAI max delta 0.001 is below the 0.2 threshold.
PP4 Not assessed: no combined, clinically calibrated multifactorial likelihood ratio for this variant was available.
Benign
BA1 Not met: the maximum group allele frequency of 5.137e-05 (gnomAD v4.1) is far below the required >0.001.
BS2 Not assessed: no homozygous or compound-heterozygous case observations or Fanconi anemia phenotype data were available.
BS3 Not assessed: no calibrated functional assay demonstrating absence of damaging effect was available for this variant.
BS4 Not assessed: no affected-relative genotypes or quantitative non-segregation data were available.
BP4 Not met: despite SpliceAI max delta 0.001, the BP4 missense pathway requires location within a clinically important domain, and residue 834 is outside them.
BP5 Not assessed: no combined, clinically calibrated multifactorial likelihood ratio against pathogenicity was available.
BP7 Not assessed: no variant-specific mRNA assay was available for BP7_Strong (RNA), and the routine BP7 pathway applies only to silent variants.
N/A · 10 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports benign
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= 6.81608e-06; MAF= 0.00068%, 11/1613830 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.88121e-05; MAF= 0.00988%, 9/91082 alleles, homozygotes = 0); grpmax FAF= 5.137e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.96724e-06; MAF= 0.00080%, 2/251028 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53595e-05; MAF= 0.00654%, 2/30600 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00068% · 11 / 1,613,830
0 hom · FAF 0.0051%
South Asian
9 / 91,082
0.0099%
Remaining individuals
1 / 62,482
0.0016%
European (non-Finnish)
1 / 1,179,986
8.5e-05%
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008% · 2 / 251,028
0 hom · FAF 0.0011%
South Asian
2 / 30,600
0.0065%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
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 (5 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 462587)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.363. BayesDel score = -0.178754.
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; COSV114744917, 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
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
26306726 ↗ Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review. CLINVAR
31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". CLINVAR
32438681 ↗ Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. CLINVAR
17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR
24366402 ↗ Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force. CLINVAR
24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR