The BRCA1 c.4530G>A (p.Met1510Ile) variant has been reported in ClinVar as a variant of uncertain significance with three clinical laboratory submissions.1 This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 1/1,614,132 alleles (AF 6.20e-07), indicating that it is very rare but not absent from population databases.2 No variant-specific calibrated functional assay result for c.4530G>A (p.Met1510Ile) was identified in the reviewed ENIGMA BRCA1 functional tables, so PS3 and BS3 were not applied.3 Computational evidence supports a benign direction under the BRCA1 ENIGMA rules because this missense change lies outside the BRCA1 clinically important domains and SpliceAI predicts no significant splice effect (max delta score 0.03), meeting BP1_Strong; BayesDel no-AF is -0.119 and does not meet the PP3 threshold, and REVEL is 0.534.4 The BRCA1 clinical-history likelihood ratio for this variant is 1.90 in one proband, which falls between the ENIGMA BP5 threshold of 0.48 and the PP4 threshold of 2.08, so neither PP4 nor BP5 was applied.5
Final classification
Uncertain Significance
BP1
BRCA1
c.4530G>A
p.Met1510Ile
This variant
The BRCA1 c.4530G>A (p.Met1510Ile) variant has been reported in ClinVar as a variant of uncertain significance with three clinical laboratory submissions.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 criteria-combination framework
Classification rationale
BP1
Uncertain Significance
BRCA1 c.4530G>A
BP1
→
Uncertain Significance
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18cspec ↗
4
cspec ↗spliceai ↗bayesdelrevel
5
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗cspec ↗
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 · 15 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
This is a missense variant outside the BRCA1 clinically important domains used by ENIGMA, and SpliceAI predicts no significant splice impact (max delta score 0.03, below the ≤0.1 threshold). This supports BP1_Strong.
Protein position 1510 is outside BRCA1 RING 2-101coiled-coil 1391-1424and BRCT 1650-1857 domains
Assessed · not applied
· 6 not met · 9 not assessed
Pathogenic
PS1
No same-amino-acid pathogenic comparator was identified from the available evidence, so PS1 was not applied.
PS3
No variant-specific calibrated functional study result supporting a damaging effect was identified in the reviewed ENIGMA BRCA1 functional tables, so PS3 was not applied.
PS4
No case-control analysis or quantified 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 but present in gnomAD v4.1 at 1/1,614,132 alleles (AF 6.20e-07; highest subpopulation AF 8.47e-07 in European non-Finnish).
PM3
No evidence was identified that this variant was observed with another BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not applied.
PP1
No segregation data were identified for this variant, so PP1 was not applied.
PP3
This missense variant lies outside the BRCA1 clinically important domains used for PP3, SpliceAI predicts no significant splice effect (max delta score 0.03; PP3 splice threshold ≥0.2), and BayesDel no-AF is -0.119, below the BRCA1 pathogenic threshold of ≥0.28.
PP4
The BRCA1 clinical-history likelihood ratio for this variant is 1.90 in 1 proband, which is below the ENIGMA PP4 threshold of 2.08.
Benign
BA1
The highest observed population frequency is 8.47e-07 in gnomAD v4.1, which is far below the BRCA1 ENIGMA BA1 threshold of FAF >0.001.
BS1
The highest observed population frequency is 8.47e-07 in gnomAD v4.1, which is below the BRCA1 ENIGMA BS1 thresholds of >2.0e-05 for BS1_Supporting and >1.0e-04 for BS1.
BS2
No qualifying observations in individuals without Fanconi anemia features were identified, so BS2 was not applied.
BS3
No variant-specific calibrated functional study result showing no damaging effect was identified in the reviewed ENIGMA BRCA1 functional tables, so BS3 was not applied.
BS4
No lack-of-segregation data were identified for this variant, so BS4 was not applied.
BP5
The BRCA1 clinical-history likelihood ratio for this variant is 1.90 in 1 proband, which is above the ENIGMA BP5 threshold of 0.48.
BP7
BP7 in this framework requires RNA evidence showing no damaging transcript effect for a qualifying variant type.
N/A · 12
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19528e-07; MAF= 0.00006%, 1/1614132 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47468e-07; MAF= 0.00008%, 1/1179986 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,132
0 hom
0 hom
European (non-Finnish) 1 / 1,179,986 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 482904)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.534. BayesDel score = -0.119197.
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.
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.
Sources & reference links
Triaged references · 9 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
12692171 ↗
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
17508274 ↗
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR