0%
Print report
Variant interpretation report

BRCA1 c.4530G>A, p.(Met1510Ile)

NM_007294.4:c.4530G>A NP_009225.1:p.(Met1510Ile) View identifiers
Classification
Uncertain significance

Variant description:

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.

In plain language

Gene-level background from the recorded interpretation.

About BRCA1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

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.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP1Strong
BP1 · strong

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.

Recorded classification: Uncertain significance

ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 criteria-combination framework

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,614,132 alleles

gnomAD v4.1: 1 / 1,614,132 alleles. Recorded AF 6.19528e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

No listed criterion applied
SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

3 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

For specialists

Technical detail

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.

Met Not met Not assessed Not applicable

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.

Met · 1

BP1 StrongThis 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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP1_Strong applies to missense variants outside clinically important domains with SpliceAI ≤0.1.
Evidence considered
  • Protein position 1510 is outside BRCA1 RING 2-101
  • coiled-coil 1391-1424
  • and BRCT 1650-1857 domains
  • SpliceAI max delta 0.03
Sources

Not met · 6 · evaluated, threshold not reached

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). Because the variant is not absent from population controls, PM2 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM2_Supporting requires absence from controls.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 AC 1/AN 1614132 total AF 6.19528018774177e-07
  • highest observed subpopulation AF 8.474676818199538e-07
Still missing
  • No gnomAD v3.1 record was provided.
Sources
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. REVEL is 0.534, but the BRCA1 ENIGMA computational rule uses BayesDel and SpliceAI, so PP3 was not met. Details ▾Hide ▴
Rule
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.
Evidence considered
  • Protein position 1510 is outside BRCA1 RING 2-101
  • coiled-coil 1391-1424
  • and BRCT 1650-1857 domains
  • SpliceAI max delta 0.03
  • BayesDel no-AF -0.119197
  • REVEL 0.534
Sources
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. This value falls in the neutral zone, so PP4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP4 uses variant-level multifactorial clinical-history likelihood ratios.
Evidence considered
  • Clinical-history LR 1.895355204218005
  • N_Probands 1
  • PP4 threshold >=2.08
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
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. BA1 was not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BA1 requires high non-founder population frequency.
Evidence considered
  • Highest observed subpopulation AF 8.474676818199538e-07
  • BA1 threshold >0.001
Still missing
  • A non-founder population FAF value was not provided
  • but the observed frequency is far below the BA1 threshold.
Sources
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. BS1 was not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS1 requires elevated non-founder population frequency.
Evidence considered
  • Highest observed subpopulation AF 8.474676818199538e-07
  • BS1 supporting threshold >0.00002
  • BS1 threshold >0.0001
Still missing
  • A non-founder population FAF value was not provided
  • but the observed frequency is far below the BS1 thresholds.
Sources
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. Because the value falls in the neutral zone, BP5 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP5 uses variant-level multifactorial clinical-history likelihood ratios.
Evidence considered
  • Clinical-history LR 1.895355204218005
  • N_Probands 1
  • BP5 threshold <=0.48
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗

Not assessed · 9 · no assessment recorded

PS1 No same-amino-acid pathogenic comparator was identified from the available evidence, so PS1 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS1 requires a previously classified pathogenic/likely pathogenic comparator with the same protein or splicing effect.
Evidence considered
  • Variant consequence p.(Met1510Ile)
  • ClinVar lists this variant as VUS
Still missing
  • A confirmed pathogenic or likely pathogenic variant producing the same amino-acid change was not identified in the reviewed materials.
Sources
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS3 requires a calibrated study showing a damaging effect.
Evidence considered
  • No c.4530G>A or p.(Met1510Ile) match found in reviewed ENIGMA Table 9 or supplementary functional table search
Still missing
  • No variant-specific protein or combined RNA/protein functional assay result was identified.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
PS4 No case-control analysis or quantified enrichment of this variant in affected individuals versus controls was identified, so PS4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS4 requires significant enrichment in affected individuals compared with controls.
Evidence considered
  • ClinVar reports the variant as VUS without case-control evidence sufficient for PS4
Still missing
  • No odds ratio
  • confidence interval
  • or p-value for this exact variant was identified.
Sources
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM3 is reserved for BRCA1/2-related Fanconi anemia cases with qualifying co-occurrence data.
Evidence considered
  • No Fanconi anemia-specific case data identified
Still missing
  • No recessive disease phenotype or phase data were identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP1 requires quantitative co-segregation evidence.
Evidence considered
  • No family segregation evidence identified
Still missing
  • No quantified co-segregation likelihood ratio or informative pedigree data were identified.
Sources
BS2 No qualifying observations in individuals without Fanconi anemia features were identified, so BS2 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS2 requires point-based evidence from observations inconsistent with recessive disease.
Evidence considered
  • No BS2-specific proband observations identified
Still missing
  • No proband-level point data for BS2 were identified.
Sources
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS3 requires a calibrated study showing no damaging effect.
Evidence considered
  • No c.4530G>A or p.(Met1510Ile) match found in reviewed ENIGMA Table 9 or supplementary functional table search
Still missing
  • No variant-specific protein or combined RNA/protein functional assay result supporting a benign effect was identified.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
BS4 No lack-of-segregation data were identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
  • No family non-segregation evidence identified
Still missing
  • No quantitative non-segregation likelihood ratio or informative pedigree data were identified.
Sources
BP7 BP7 in this framework requires RNA evidence showing no damaging transcript effect for a qualifying variant type. No variant-specific RNA study was identified for this missense change, so BP7 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 requires qualifying RNA evidence and does not rely on prediction alone.
Evidence considered
  • SpliceAI max delta 0.03
  • No reviewed variant-specific RNA assay match identified
Still missing
  • No variant-specific mRNA assay result was identified.
Sources
cspec ↗spliceai ↗vcep_supplementarytables_v1_2_2024_11_18
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ABRCA1 loss of function is an established disease mechanism, but this variant is a missense substitution, not a nonsense, frameshift, initiation-loss, or canonical ±1,2 splice variant. Available data therefore do not place this variant into the ENIGMA BRCA1 PVS1 framework. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PVS1 applies to null variants or RNA evidence showing a loss-of-function transcript effect.
Evidence considered
  • BRCA1 PVS1 gene gate eligible
  • c.4530G>A encodes p.(Met1510Ile)
  • not a null or canonical splice-consensus variant
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessment
PS2 VCEPDe novo evidence is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
VCEP rule
PS2 not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
  • PS2 listed as not applicable in the BRCA1 ENIGMA specification
Sources
PM1 VCEPPM1 is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
VCEP rule
PM1 not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
  • PM1 listed as not applicable in the BRCA1 ENIGMA specification
Sources
PM4 VCEPPM4 is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
VCEP rule
PM4 not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
  • PM4 listed as not applicable in the BRCA1 ENIGMA specification
Sources
PM5 N/AIn this ENIGMA BRCA1 framework, PM5 is repurposed for protein-terminating variants in exons with prior proven pathogenic truncating variants. This variant is a missense substitution, so PM5 does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM5 applies to qualifying PTC variants rather than classic same-residue missense PM5.
Evidence considered
  • pm5_mode=ptc_gene_specific
  • eligible_for_classic_pm5_search=false
  • variant is missense p.(Met1510Ile)
Sources
cspec ↗pm5_candidates
PM6 VCEPDe novo evidence is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
VCEP rule
PM6 not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
  • PM6 listed as not applicable in the BRCA1 ENIGMA specification
Sources
PP2 VCEPPP2 is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
VCEP rule
PP2 not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
  • PP2 listed as not applicable in the BRCA1 ENIGMA specification
Sources
PP5 VCEPPP5 is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
VCEP rule
PP5 not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
  • PP5 listed as not applicable in the BRCA1 ENIGMA specification
Sources
BP2 VCEPBP2 is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
VCEP rule
BP2 not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
  • BP2 listed as not applicable in the BRCA1 ENIGMA specification
Sources
BP3 VCEPBP3 is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
VCEP rule
BP3 not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
  • BP3 listed as not applicable in the BRCA1 ENIGMA specification
Sources
BP4 N/AFor BRCA1 missense variants, BP4 is reserved for variants inside a clinically important functional domain with no predicted protein or splice impact. This variant lies outside those domains, so BP4 does not apply; the framework instead captures this pattern with BP1. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 missense application is limited to variants inside clinically important domains.
Evidence considered
  • Protein position 1510 outside BRCA1 clinically important domains
  • SpliceAI max delta 0.03
  • BayesDel no-AF -0.119197
Sources
BP6 VCEPBP6 is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
VCEP rule
BP6 not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
  • BP6 listed as not applicable in the BRCA1 ENIGMA specification
Sources

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.4530G>A
Protein (HGVS p.)
NP_009225.1:p.(Met1510Ile)
GRCh38
chr17:43074476 C>T
GRCh37
chr17:41226493 C>T
ClinVar
3481882, 1655383, 1611577, 1137858, 482910, 482904, 427351, 415553

Gene diagram

Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.

BRCA1NM_007294.4
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,614,132 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,132 alleles · 0 hom
European (non-Finnish)1 / 1,179,986 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

SpliceAI and Pangolin

SpliceAI acceptor lossat +16 bp
0.030
SpliceAI acceptor gainat +437 bp
0.000
SpliceAI donor lossat -134 bp
0.010
SpliceAI donor gainat +368 bp
0.000
Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.000

Other predictors

REVEL
0.534
BayesDel
-0.119

How the predictions were used

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. REVEL is 0.534, but the BRCA1 ENIGMA computational rule uses BayesDel and SpliceAI, so PP3 was not met. Details ▾Hide ▴
Rule
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.
Evidence considered
  • Protein position 1510 is outside BRCA1 RING 2-101
  • coiled-coil 1391-1424
  • and BRCT 1650-1857 domains
  • SpliceAI max delta 0.03
  • BayesDel no-AF -0.119197
  • REVEL 0.534
Sources
BP7 BP7 in this framework requires RNA evidence showing no damaging transcript effect for a qualifying variant type. No variant-specific RNA study was identified for this missense change, so BP7 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 requires qualifying RNA evidence and does not rely on prediction alone.
Evidence considered
  • SpliceAI max delta 0.03
  • No reviewed variant-specific RNA assay match identified
Still missing
  • No variant-specific mRNA assay result was identified.
Sources
cspec ↗spliceai ↗vcep_supplementarytables_v1_2_2024_11_18
BP4 N/AFor BRCA1 missense variants, BP4 is reserved for variants inside a clinically important functional domain with no predicted protein or splice impact. This variant lies outside those domains, so BP4 does not apply; the framework instead captures this pattern with BP1. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 missense application is limited to variants inside clinically important domains.
Evidence considered
  • Protein position 1510 outside BRCA1 clinically important domains
  • SpliceAI max delta 0.03
  • BayesDel no-AF -0.119197
Sources

Statement

In silico

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.

Recorded publications

  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
    No paper-specific finding is recorded.
    PMID 23918944 ↗
  • 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.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
    American Society of Clinical Oncology · 2003
    No paper-specific finding is recorded.
    PMID 12692171 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
    Saslow D et al. · 2007
    No paper-specific finding is recorded.
    PMID 17392385 ↗
  • Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
    No paper-specific finding is recorded.
    PMID 17508274 ↗
  • The emerging landscape of breast cancer susceptibility.
    No paper-specific finding is recorded.
    PMID 18163131 ↗
  • ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.
    No paper-specific finding is recorded.
    PMID 19305347 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.