About BRCA1
No gene-level summary was recorded for this case.
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.No gene-level summary was recorded for this case.
The recorded framework is ClinGen BRCA1 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
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.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 criteria-combination framework
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1 / 1,614,132 alleles. Recorded AF 6.19528e-07. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
3 Uncertain significance.
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.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 6 not met · 9 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The BRCA1 c.4530G>A (p.Met1510Ile) variant has been reported in ClinVar as a variant of uncertain significance with three clinical laboratory submissions.
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.
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.
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.
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.
No criteria match.
ENIGMA BRCA1 BP1_Strong applies to missense variants outside clinically important domains with SpliceAI ≤0.1.
ENIGMA BRCA1 PM2_Supporting requires absence from controls.
ENIGMA BRCA1 PP3 applies to missense variants inside clinically important domains with BayesDel no-AF ≥0.28, or to predicted splice impact with SpliceAI ≥0.2.
ENIGMA BRCA1 PP4 uses variant-level multifactorial clinical-history likelihood ratios.
ENIGMA BRCA1 BA1 requires high non-founder population frequency.
ENIGMA BRCA1 BS1 requires elevated non-founder population frequency.
ENIGMA BRCA1 BP5 uses variant-level multifactorial clinical-history likelihood ratios.
ENIGMA BRCA1 PS1 requires a previously classified pathogenic/likely pathogenic comparator with the same protein or splicing effect.
ENIGMA BRCA1 PS3 requires a calibrated study showing a damaging effect.
ENIGMA BRCA1 PS4 requires significant enrichment in affected individuals compared with controls.
ENIGMA BRCA1 PM3 is reserved for BRCA1/2-related Fanconi anemia cases with qualifying co-occurrence data.
ENIGMA BRCA1 PP1 requires quantitative co-segregation evidence.
ENIGMA BRCA1 BS2 requires point-based evidence from observations inconsistent with recessive disease.
ENIGMA BRCA1 BS3 requires a calibrated study showing no damaging effect.
ENIGMA BRCA1 BS4 requires quantitative lack-of-segregation evidence.
ENIGMA BRCA1 BP7 requires qualifying RNA evidence and does not rely on prediction alone.
ENIGMA BRCA1 PVS1 applies to null variants or RNA evidence showing a loss-of-function transcript effect.
PS2 not applicable in ENIGMA BRCA1 v1.2.
PM1 not applicable in ENIGMA BRCA1 v1.2.
PM4 not applicable in ENIGMA BRCA1 v1.2.
ENIGMA BRCA1 PM5 applies to qualifying PTC variants rather than classic same-residue missense PM5.
PM6 not applicable in ENIGMA BRCA1 v1.2.
PP2 not applicable in ENIGMA BRCA1 v1.2.
PP5 not applicable in ENIGMA BRCA1 v1.2.
BP2 not applicable in ENIGMA BRCA1 v1.2.
BP3 not applicable in ENIGMA BRCA1 v1.2.
ENIGMA BRCA1 BP4 missense application is limited to variants inside clinically important domains.
BP6 not applicable in ENIGMA BRCA1 v1.2.
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)1 / 1,179,986 | 8.5e-07 |
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).
Absent from gnomAD v2.1.
ENIGMA BRCA1 PP3 applies to missense variants inside clinically important domains with BayesDel no-AF ≥0.28, or to predicted splice impact with SpliceAI ≥0.2.
ENIGMA BRCA1 BP7 requires qualifying RNA evidence and does not rely on prediction alone.
ENIGMA BRCA1 BP4 missense application is limited to variants inside clinically important domains.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.534. BayesDel score = -0.119197.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
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).
Absent from gnomAD v2.1.
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 482904)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.534. BayesDel score = -0.119197.
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.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.