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BRCA1c.4987-7A>GLikely pathogenic
Print report
Variant interpretation report

BRCA1 c.4987-7A>G, p.?

NM_007294.3:c.4987-7A>G NP_009225.1:p.? View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

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: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Strong
PS3 · strong

In a calibrated functional study that incorporated mRNA splicing effects, this intronic variant showed complete functional impact/loss of function and protein function similar to pathogenic control variants, supporting a damaging effect. The ENIGMA BRCA1 specification lists this exact variant as PS3 at strong strength.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population databases and meets the ENIGMA PM2_Supporting rule.

PP3Supporting
PP3 · supporting

SpliceAI predicts a splice effect with a maximum delta score of 0.65, which is above the ENIGMA PP3 threshold of 0.2 for intronic variants outside the donor and acceptor +/-1,2 positions. This supports a predicted abnormal splicing effect.

PP5Supporting
PP5 · supporting

Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Official ClinGen ENIGMA BRCA1/BRCA2 final-classification framework from Table 3 override in the CSPEC-derived final_classification_framework was applied.

02The sources

Evidence at a glance

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

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · PP3 →
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

Applied · PS3 → OncoKB ↗
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Context only COSMIC ↗
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: 4 met · 5 not met · 9 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The BRCA1 c.4987-7A>G (NP_009225.1:p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, including a ClinGen ENIGMA expert panel classification of likely pathogenic.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting ENIGMA PM2_Supporting.

In a calibrated functional study incorporating mRNA splicing effects, this intronic variant showed complete functional impact/loss of function consistent with pathogenic control variants, and the ENIGMA BRCA1 specification assigns PS3 at strong strength for this exact variant.

SpliceAI predicts an abnormal splicing effect with a maximum delta score of 0.65, which is above the ENIGMA PP3 threshold of 0.2 and argues against BP4 or BP7.

Met · 4

PS3 StrongIn a calibrated functional study that incorporated mRNA splicing effects, this intronic variant showed complete functional impact/loss of function and protein function similar to pathogenic control variants, supporting a damaging effect. The ENIGMA BRCA1 specification lists this exact variant as PS3 at strong strength. Details ▾Hide ▴
Rule
Well-established functional studies supportive of a damaging effect support PS3; for this exact variant ENIGMA Table 9 assigns PS3 Strong.
Evidence considered
  • Specifications Table 9 lists BRCA1 c.4987-7A>G as PS3 Strong.
  • Supplementary Table 4 records BRCA1 c.4987-7A>G as Functional impact - complete / LOF.
  • The cited calibrated study is Findlay 2018.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population databases and meets the ENIGMA PM2_Supporting rule. Details ▾Hide ▴
Rule
ENIGMA PM2_Supporting applies when the variant is absent from gnomAD controls with adequate coverage context.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PP3 SupportingSpliceAI predicts a splice effect with a maximum delta score of 0.65, which is above the ENIGMA PP3 threshold of 0.2 for intronic variants outside the donor and acceptor +/-1,2 positions. This supports a predicted abnormal splicing effect. Details ▾Hide ▴
Rule
ENIGMA PP3 applies to predicted splicing variants with SpliceAI >=0.2.
Evidence considered
  • SpliceAI DS_AL 0.65
  • max delta score 0.65.
  • Variant position is c.4987-7
  • outside canonical +/-1
  • 2.
Sources
cspec ↗spliceai ↗
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • CSPEC marks PP5 as not applicable.
  • ClinVar expert panel classification
Sources
cspec ↗clinvar ↗

Not met · 5 · evaluated, threshold not reached

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the ENIGMA BA1 threshold of filter allele frequency greater than 0.1%. Details ▾Hide ▴
Rule
ENIGMA BA1 requires FAF >0.001.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the ENIGMA BS1 thresholds of filter allele frequency above 0.002% or 0.01%. Details ▾Hide ▴
Rule
ENIGMA BS1 requires FAF >0.00002 for supporting or >0.0001 for strong.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 Available functional evidence does not support a benign effect. Instead, the retrieved calibrated functional data support a damaging splice-related loss-of-function effect. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Evidence considered
  • Table 9 assigns PS3 Strong
  • not BS3.
  • Supplementary Table 4 records Functional impact - complete / LOF.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗
BP4 SpliceAI predicts a splice effect with a maximum delta score of 0.65, which is above the ENIGMA BP4 threshold of 0.1 for intronic variants outside the canonical splice sites. Available computational evidence therefore does not support a benign splicing prediction. Details ▾Hide ▴
Rule
ENIGMA BP4 for intronic variants outside +/-1,2 requires SpliceAI <=0.1.
Evidence considered
  • SpliceAI max delta score 0.65.
Sources
cspec ↗spliceai ↗
BP7 This intronic variant is at position -7, which is not in the ENIGMA BP7 supporting zone for intronic variants at or beyond -21/+7, and computational evidence predicts splice disruption rather than no impact. No benign RNA assay result was identified. Details ▾Hide ▴
Rule
ENIGMA BP7 supporting for intronic variants requires location at or beyond +7/-21 with BP4 met, or strong benign RNA evidence.
Evidence considered
  • Variant position is c.4987-7.
  • SpliceAI max delta score 0.65.
Sources
cspec ↗spliceai ↗

Not assessed · 9 · no assessment recorded

PVS1 This intronic variant is outside the canonical +/-1,2 splice consensus positions, and the generic PVS1 scaffold does not place it in a default null-variant category. Available functional evidence supports a damaging splice effect, but the retrieved evidence does not provide a formal ENIGMA PVS1(RNA) strength assignment for this specific non-canonical intronic change. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PVS1 applies to null variants with strength determined by the PVS1 flowchart and exon context; the generic scaffold does not auto-qualify this non-canonical intronic variant.
Evidence considered
  • BRCA1 is eligible for PVS1 within the ENIGMA framework.
  • The variant is c.4987-7A>G
  • not a canonical +/-1
  • 2 splice-site variant.
  • Generic PVS1 scaffold states this variant does not fall into the default null-variant buckets.
Still missing
  • Formal ENIGMA RNA-based PVS1 weighting for this exact variant was not identified in the retrieved materials.
  • Detailed transcript-level quantitation needed for PVS1(RNA) weighting was not retrieved.
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PS1 No directly comparable pathogenic or likely pathogenic variant with the same demonstrated splicing consequence was identified in the retrieved evidence, so PS1 was not established. Details ▾Hide ▴
Rule
ENIGMA PS1 for exonic or intronic variants requires the same predicted splicing impact as a previously classified pathogenic or likely pathogenic variant.
Evidence considered
  • PS1 in this specification requires the same protein effect or the same predicted splicing impact as a previously classified pathogenic or likely pathogenic variant.
Still missing
  • No curated same-splicing-effect comparator variant was retrieved.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS4 No case-control study or odds ratio data showing significantly increased prevalence in affected individuals were identified, so PS4 was not established. Details ▾Hide ▴
Rule
ENIGMA PS4 requires statistically significant case-control enrichment.
Evidence considered
  • ENIGMA PS4 requires case-control evidence with p<=0.05 and OR>=4 with lower confidence interval excluding 2.0.
Still missing
  • No qualifying case-control evidence with OR and confidence interval was retrieved.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM3 No evidence was identified for biallelic occurrence in a patient with BRCA1-related Fanconi anemia, so PM3 was not established. Details ▾Hide ▴
Rule
ENIGMA PM3 is based on a point system for Fanconi anemia probands.
Evidence considered
  • ENIGMA PM3 is reserved for BRCA1/2-related Fanconi anemia cases with qualifying co-occurring variants.
Still missing
  • No proband-level Fanconi anemia data or phase data were retrieved.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP1 No quantitative segregation data were identified, so PP1 was not established. Details ▾Hide ▴
Rule
ENIGMA PP1 is assigned by segregation likelihood ratio thresholds.
Evidence considered
  • ENIGMA PP1 requires quantitative segregation analysis with likelihood ratio thresholds.
Still missing
  • No co-segregation likelihood ratio data were retrieved.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP4 No variant-specific clinical-history likelihood ratio meeting ENIGMA thresholds was identified, so PP4 was not established. Details ▾Hide ▴
Rule
ENIGMA PP4 requires variant-specific multifactorial clinical likelihood ratio >=2.08.
Evidence considered
  • No match for c.4987-7A>G was identified in the BRCA1 clinical-history LR workbook.
Still missing
  • No matching entry for this variant was retrieved from the BRCA1 clinical-history LR table.
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
BS2 No unaffected adult or recessive disease exclusion data meeting the BRCA1 ENIGMA point system were identified, so BS2 was not established. Details ▾Hide ▴
Rule
ENIGMA BS2 is assigned by a point system.
Evidence considered
  • ENIGMA BS2 requires point-based evidence in the absence of Fanconi anemia features.
Still missing
  • No BS2 point-based proband evidence was retrieved.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS4 No quantitative lack-of-segregation evidence was identified, so BS4 was not established. Details ▾Hide ▴
Rule
ENIGMA BS4 is assigned by segregation likelihood ratio thresholds.
Evidence considered
  • ENIGMA BS4 requires quantitative segregation evidence.
Still missing
  • No segregation likelihood ratio data against pathogenicity were retrieved.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP5 No variant-specific clinical-history likelihood ratio in the benign direction was identified, so BP5 was not established. Details ▾Hide ▴
Rule
ENIGMA BP5 requires variant-specific multifactorial clinical likelihood ratio <=0.48.
Evidence considered
  • No match for c.4987-7A>G was identified in the BRCA1 clinical-history LR workbook.
Still missing
  • No matching entry for this variant was retrieved from the BRCA1 clinical-history LR table.
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • CSPEC marks PS2 as not applicable.
Sources
cspec ↗
PM1 N/AThis criterion is not applicable for this BRCA1 intronic splice-region variant in the ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP in this variant context.
Evidence considered
  • CSPEC marks PM1 as not applicable.
Sources
cspec ↗
PM4 N/AThis criterion is not applicable because the variant is not an in-frame protein length change. Details ▾Hide ▴
Rule
Not applicable for this variant type.
Evidence considered
  • CSPEC marks PM4 as not applicable.
Sources
cspec ↗
PM5 N/AIn the ENIGMA BRCA1 specification, PM5 is used for protein-terminating variants already annotated as PVS1. This intronic splice-region variant is not a protein-terminating variant in that framework context. Details ▾Hide ▴
Rule
ENIGMA PM5 applies to PTC variants in exons where a different proven pathogenic PTC has been observed.
Evidence considered
  • ENIGMA PM5 here is a PM5_PTC rule for PTC variants in eligible exons.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
PM6 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • CSPEC marks PM6 as not applicable.
Sources
cspec ↗
PP2 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • CSPEC marks PP2 as not applicable.
Sources
cspec ↗
BP1 N/AThis criterion is intended for silent, missense, or in-frame variants without predicted splice impact and does not apply to this intronic splice-region variant. Details ▾Hide ▴
Rule
Not applicable for this intronic splice-region variant.
Evidence considered
  • ENIGMA BP1 applies to silent
  • missense
  • or in-frame variants outside key domains with SpliceAI <=0.1.
Sources
cspec ↗
BP2 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • CSPEC marks BP2 as not applicable.
Sources
cspec ↗
BP3 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • CSPEC marks BP3 as not applicable.
Sources
cspec ↗
BP6 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • CSPEC marks BP6 as not applicable.
Sources
cspec ↗

Identifiers

Gene
BRCA1
Transcript
NM_007294.3
Coding (HGVS c.)
NM_007294.3:c.4987-7A>G
Protein (HGVS p.)
NP_009225.1:p.?
GRCh38
chr17:43067702 T>C
GRCh37
chr17:41219719 T>C

Gene diagram

Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.3. Select a row to find it on the plot.

BRCA1NM_007294.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SupportingSpliceAI predicts a splice effect with a maximum delta score of 0.65, which is above the ENIGMA PP3 threshold of 0.2 for intronic variants outside the donor and acceptor +/-1,2 positions. This supports a predicted abnormal splicing effect. Details ▾Hide ▴
Rule
ENIGMA PP3 applies to predicted splicing variants with SpliceAI >=0.2.
Evidence considered
  • SpliceAI DS_AL 0.65
  • max delta score 0.65.
  • Variant position is c.4987-7
  • outside canonical +/-1
  • 2.
Sources
cspec ↗spliceai ↗
BP4 SpliceAI predicts a splice effect with a maximum delta score of 0.65, which is above the ENIGMA BP4 threshold of 0.1 for intronic variants outside the canonical splice sites. Available computational evidence therefore does not support a benign splicing prediction. Details ▾Hide ▴
Rule
ENIGMA BP4 for intronic variants outside +/-1,2 requires SpliceAI <=0.1.
Evidence considered
  • SpliceAI max delta score 0.65.
Sources
cspec ↗spliceai ↗
BP7 This intronic variant is at position -7, which is not in the ENIGMA BP7 supporting zone for intronic variants at or beyond -21/+7, and computational evidence predicts splice disruption rather than no impact. No benign RNA assay result was identified. Details ▾Hide ▴
Rule
ENIGMA BP7 supporting for intronic variants requires location at or beyond +7/-21 with BP4 met, or strong benign RNA evidence.
Evidence considered
  • Variant position is c.4987-7.
  • SpliceAI max delta score 0.65.
Sources
cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.65).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.65).

Somatic

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