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NM_007294.4:c.3001G>A
p.Glu1001Lys · 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.3001G>A
p.Glu1001Lys
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

This BRCA1 variant affects a tumor-suppressor gene responsible for homologous-recombination DNA repair and hereditary breast and ovarian cancer susceptibility.

Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.3001G>A
GRCh38
chr17:43092530 C>T
GRCh37
chr17:41244547 C>T
VUS: BP1 (strong) is the only met criterion, with no qualifying pathogenic evidence or additional benign evidence to satisfy ENIGMA's combination rules.
Classification rationale
BP1 VUS
BRCA1 c.3001G>A missense · exon 10

VUS: BP1 (strong) is met because residue 1001 is outside approved BRCA1 domains and SpliceAI max delta is 0.004. VUS: no pathogenic criterion is met, and BP1 (strong) lacks the additional benign evidence required for a benign call.

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 · 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 at Strong: residue 1001 is outside approved domains and SpliceAI max delta 0.004 meets the ≤0.1 no-splicing requirement.
Specifications v1.2, BP1_Strong rule: applies to missense variants outside a potentially clinically important functional domain with no predicted splicing (SpliceAI ≤0.1); missense prediction is not applicable.Approved BRCA1 domains checked: RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Glu1001Lys at aa 1001 is outside every listed domain.SpliceAI case result: DS_AG 0.004, DS_AL 0.000, DS_DG 0.000, DS_DL 0.001; maximum delta score 0.004.
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗spliceai ↗
Assessed · not applied · 4 not met · 10 not assessed
Pathogenic
PS1 Not met: no VCEP-recorded pathogenic or likely pathogenic variant was identified with the same p.Glu1001Lys amino-acid substitution.
PS3 Not assessed: no exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in the governing functional tables.
PS4 Not assessed: no variant-specific case-control odds ratio, p-value, or confidence interval is available for the required PS4 comparison.
PM2 Not assessed: the variant is absent from required gnomAD non-cancer datasets, but regional average read depth of at least 25 is not documented.
PM3 Not assessed: no documented same-gene pathogenic/likely pathogenic co-occurring variant, phase, or Fanconi Anemia phenotype is available to assign the VCEP's PM3 points.
PP1 Not assessed: no quantitative cosegregation LR or affected-family genotype data are available to compare with the VCEP PP1 threshold of LR ≥2.08:1.
PP3 Not met: SpliceAI maximum delta 0.004 is below the VCEP PP3 splice threshold of ≥0.2 for this missense variant.
PP4 Not assessed: no combined clinical likelihood ratio is available, and the Li et al.
Benign
BA1 Not met: the qualifying gnomAD non-cancer datasets report no variant, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 0.001.
BS1 Not met: the qualifying gnomAD non-cancer datasets report no variant, so no filter allele frequency exceeds the ENIGMA BS1 threshold of 0.00002.
BS2 Not assessed: no healthy-adult genotype observations or ENIGMA BS2 point count is available to reach the required threshold of 1, 2, or 4 points.
BS3 Not assessed: no exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in the governing functional tables.
BS4 Not assessed: no quantitative negative-cosegregation LR or affected-family genotype data are available to compare with the VCEP BS4 threshold of LR ≤0.48:1.
BP5 Not assessed: no combined clinical likelihood ratio is available, and the Li et al.
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
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 screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 822554)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.417. BayesDel score = -0.163974.
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 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 · 6 PMIDs not cited in assessment
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
24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR
24432435 ↗ PMID 24432435 CLINVAR
24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR