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BRCA1c.442-22_442-13delLikely pathogenic
Print report
Variant interpretation report

BRCA1 c.442-22_442-13del, p.?

NM_007294.4:c.442-22_442-13del 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
PVS1Strong
PVS1 · strong

This intronic deletion has published RNA evidence showing insertion of 59 nucleotides from intron 7, producing a frameshift and premature termination of BRCA1. Because loss of function is an established disease mechanism for BRCA1, this supports PVS1 at RNA-based strong weight for a non-canonical splice variant, although the proportion of functional transcript retained was not quantitatively reported.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls consistent with PM2_Supporting under the BRCA1 ENIGMA framework.

PP3Supporting
PP3 · supporting

SpliceAI predicts splice disruption for this intronic variant with a maximum delta score of 0.66, which is above the ENIGMA PP3 threshold of 0.2 for non-canonical intronic variants and supports a deleterious splicing effect.

PP5Supporting
PP5 · supporting

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

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ClinGen ENIGMA BRCA1/2 VCEP v1.2 Table 3 final-classification framework was applied. PVS1_Strong with PM2_Supporting, PP3_Supporting, and PP5_Supporting satisfies the Likely Pathogenic combination of one Strong pathogenic criterion plus at least two Supporting pathogenic criteria.

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.

No listed criterion applied 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 · 4 not met · 10 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.442-22_442-13del (NP_009225.1:p.?) variant has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.

Published RNA studies reported that this intronic deletion inserts 59 nucleotides from intron 7 and causes a frameshift with premature termination, and later functional work showed an impaired DNA-damage response associated with the variant.

SpliceAI predicts splice disruption with a maximum delta score of 0.66, which is above the ENIGMA PP3 threshold of 0.2 for non-canonical intronic variants.

Met · 4

PVS1 StrongThis intronic deletion has published RNA evidence showing insertion of 59 nucleotides from intron 7, producing a frameshift and premature termination of BRCA1. Because loss of function is an established disease mechanism for BRCA1, this supports PVS1 at RNA-based strong weight for a non-canonical splice variant, although the proportion of functional transcript retained was not quantitatively reported. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 VCEP PVS1_Variable Weight (RNA) for non-canonical splice variants with damaging mRNA evidence
Evidence considered
  • ENIGMA BRCA1/2 VCEP PVS1 RNA framework for non-canonical splice variants
  • Published RNA study reporting a 59-nt intron 7 insertion with frameshift and premature termination
Still missing
  • Published RNA results did not provide allele-specific transcript quantification
  • so exact RNA weighting remains appropriate for manual confirmation.
Sources
cspec ↗PMID:10323242 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls consistent with PM2_Supporting under the BRCA1 ENIGMA framework. Details ▾Hide ▴
Rule
ENIGMA PM2_Supporting requires absence from population controls
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 absent
Still missing
  • The available population summaries do not report the region-level read-depth metric specified in the ENIGMA text
  • so final confirmation of depth can be reviewed if needed.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PP3 SupportingSpliceAI predicts splice disruption for this intronic variant with a maximum delta score of 0.66, which is above the ENIGMA PP3 threshold of 0.2 for non-canonical intronic variants and supports a deleterious splicing effect. Details ▾Hide ▴
Rule
ENIGMA PP3 splice prediction rule
Evidence considered
  • SpliceAI max delta score 0.66
  • ENIGMA PP3 threshold for predicted splicing impact is at least 0.2
Sources
cspec ↗spliceai ↗
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Rule
ENIGMA BRCA1 specification
Evidence considered
  • ENIGMA BRCA1 specification lists PP5 as not applicable
  • ClinVar expert panel classification
Sources
cspec ↗clinvar ↗

Not met · 4 · 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 population threshold
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 absent
  • BA1 threshold FAF >0.001
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% in a non-founder population. Details ▾Hide ▴
Rule
ENIGMA BS1 population threshold
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 absent
  • BS1 thresholds require observed population frequency above specified cutoffs
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP4 SpliceAI predicts splice impact for this intronic variant with a maximum delta score of 0.66, which is above the ENIGMA BP4 threshold of 0.1 for no predicted splice impact, so BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BP4 splice prediction rule
Evidence considered
  • SpliceAI max delta score 0.66
  • BP4 requires SpliceAI 0.1 or lower for intronic variants
Sources
cspec ↗spliceai ↗
BP7 This intronic deletion does not meet BP7 because benign splicing evidence was not identified and BP4 is not met; SpliceAI predicts splice impact with a maximum delta score of 0.66 rather than the no-impact profile required for BP7 application. Details ▾Hide ▴
Rule
ENIGMA BP7 RNA/benign splicing rule
Evidence considered
  • SpliceAI max delta score 0.66
  • BP7 for intronic variants requires a benign splicing context and BP4 support
Sources
cspec ↗spliceai ↗

Not assessed · 10 · no assessment recorded

PS1 Available evidence does not establish that this variant has the same predicted splicing consequence as a different previously classified pathogenic or likely pathogenic variant under the ENIGMA PS1 framework. Details ▾Hide ▴
Rule
ENIGMA PS1 splice-equivalence rule
Evidence considered
  • ENIGMA PS1 framework allows use for intronic variants only when the same splicing impact as a previously classified variant is established
Still missing
  • No matched reference splice variant with the same validated splicing consequence was identified from the available materials.
Sources
cspec ↗
PS3 Available functional evidence for this variant is primarily splicing and transcript-based, which is captured under the ENIGMA RNA framework rather than applying PS3 directly from the available materials. Details ▾Hide ▴
Rule
ENIGMA PS3 protein or combined protein/mRNA functional evidence rule
Evidence considered
  • ENIGMA distinguishes mRNA-only evidence from protein-based PS3 evidence
  • Published study reported impaired DNA repair response but no direct ENIGMA PS3 code assignment was available
Still missing
  • No calibrated ENIGMA PS3 assignment for this specific variant was identified in the available functional tables.
Sources
cspec ↗PMID:32745242 ↗
PS4 This variant has been reported in affected families, but the available evidence does not provide the case-control statistics or ENIGMA-calibrated proband-counting data required to apply PS4. Details ▾Hide ▴
Rule
ENIGMA PS4 prevalence/case-control rule
Evidence considered
  • Published family observations
  • ENIGMA PS4 requires case-control or calibrated counting evidence
Still missing
  • No odds ratio
  • confidence interval
  • or validated ENIGMA PS4 counting dataset was identified.
Sources
cspec ↗PMID:32745242 ↗
PM3 No evidence was identified showing this variant in trans with another BRCA1 variant in an individual with BRCA1-related Fanconi anemia features, so PM3 cannot be assessed from the available data. Details ▾Hide ▴
Rule
ENIGMA PM3 Fanconi anemia rule
Evidence considered
  • ENIGMA PM3 is restricted to BRCA1/2-related Fanconi anemia context
Still missing
  • No biallelic BRCA1 Fanconi anemia case data were identified.
Sources
cspec ↗
PP1 Segregation has been mentioned in the literature, but no quantitative segregation likelihood ratio was available from the reviewed materials to support PP1 at any ENIGMA strength. Details ▾Hide ▴
Rule
ENIGMA PP1 quantitative segregation rule
Evidence considered
  • Published statement that segregation analysis contributed to reclassification
  • ENIGMA PP1 requires quantitative segregation analysis
Still missing
  • No validated segregation likelihood ratio or pedigree-based ENIGMA calculation was identified.
Sources
cspec ↗PMID:32745242 ↗
PP4 Although this variant has been observed in families with hereditary breast and ovarian cancer, no exact variant-level clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified in the available structured resources. Details ▾Hide ▴
Rule
ENIGMA PP4 multifactorial clinical-history LR rule
Evidence considered
  • ENIGMA PP4 requires calibrated multifactorial clinical likelihood ratios
Still missing
  • No exact match for this variant was identified in the BRCA1 clinical-history likelihood-ratio table.
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
BS2 No evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia in the biallelic context required for ENIGMA BS2. Details ▾Hide ▴
Rule
ENIGMA BS2 Fanconi anemia rule
Evidence considered
  • ENIGMA BS2 is restricted to biallelic BRCA1/2 assessment context
Still missing
  • No BS2 point-based Fanconi anemia context data were identified.
Sources
cspec ↗
BS3 No well-established functional study showing no damaging effect was identified for this variant, so BS3 is not supported by the available evidence. Details ▾Hide ▴
Rule
ENIGMA BS3 functional evidence rule
Evidence considered
  • No benign functional assignment found in the available ENIGMA materials
Still missing
  • No benign functional or RNA study result meeting ENIGMA BS3 or BP7 RNA criteria was identified.
Sources
cspec ↗
BS4 No quantitative evidence showing lack of segregation with disease was identified, so BS4 cannot be applied from the available materials. Details ▾Hide ▴
Rule
ENIGMA BS4 quantitative segregation rule
Evidence considered
  • ENIGMA BS4 requires quantitative lack-of-segregation evidence
Still missing
  • No benign-direction segregation likelihood ratio was identified.
Sources
cspec ↗
BP5 No exact variant-level clinical-history likelihood ratio meeting ENIGMA BP5 benign thresholds was identified in the available structured resources. Details ▾Hide ▴
Rule
ENIGMA BP5 multifactorial clinical-history LR rule
Evidence considered
  • ENIGMA BP5 requires calibrated multifactorial clinical likelihood ratios in the benign direction
Still missing
  • No exact match for this variant was identified in the BRCA1 clinical-history likelihood-ratio 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
ENIGMA BRCA1 specification
Evidence considered
  • ENIGMA BRCA1 specification lists PS2 as not applicable
Sources
cspec ↗
PM1 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 specification
Evidence considered
  • ENIGMA BRCA1 specification lists PM1 as not applicable
Sources
cspec ↗
PM4 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 specification
Evidence considered
  • ENIGMA BRCA1 specification lists PM4 as not applicable
Sources
cspec ↗
PM5 N/AENIGMA PM5 in BRCA1 is used for protein termination codon variants by exon-based weighting. This intronic deletion is not directly a protein termination codon variant in the submitted DNA description, so PM5 was not applied from the available evidence. Details ▾Hide ▴
Rule
ENIGMA PM5_PTC exon-based rule
Evidence considered
  • ENIGMA PM5_PTC framework is exon-based for protein termination codon variants
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 specification
Evidence considered
  • ENIGMA BRCA1 specification lists PM6 as not applicable
Sources
cspec ↗
PP2 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 specification
Evidence considered
  • ENIGMA BRCA1 specification lists PP2 as not applicable
Sources
cspec ↗
BP1 N/AENIGMA BP1 is intended for silent, missense, or in-frame variants outside key functional domains without predicted splice impact, and it does not apply to this intronic deletion. Details ▾Hide ▴
Rule
ENIGMA BP1 variant-type restriction
Evidence considered
  • Variant type is intronic rather than silent
  • missense
  • or in-frame
Sources
cspec ↗
BP2 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 specification
Evidence considered
  • ENIGMA BRCA1 specification lists BP2 as not applicable
Sources
cspec ↗
BP3 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 specification
Evidence considered
  • ENIGMA BRCA1 specification lists BP3 as not applicable
Sources
cspec ↗
BP6 N/AThis criterion is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 specification
Evidence considered
  • ENIGMA BRCA1 specification lists BP6 as not applicable
Sources
cspec ↗

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.442-22_442-13del
Protein (HGVS p.)
NP_009225.1:p.?
GRCh38
chr17:43099892 GGTAAAGAACA>G
GRCh37
chr17:41251909 GGTAAAGAACA>G

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 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 splice disruption for this intronic variant with a maximum delta score of 0.66, which is above the ENIGMA PP3 threshold of 0.2 for non-canonical intronic variants and supports a deleterious splicing effect. Details ▾Hide ▴
Rule
ENIGMA PP3 splice prediction rule
Evidence considered
  • SpliceAI max delta score 0.66
  • ENIGMA PP3 threshold for predicted splicing impact is at least 0.2
Sources
cspec ↗spliceai ↗
BP4 SpliceAI predicts splice impact for this intronic variant with a maximum delta score of 0.66, which is above the ENIGMA BP4 threshold of 0.1 for no predicted splice impact, so BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BP4 splice prediction rule
Evidence considered
  • SpliceAI max delta score 0.66
  • BP4 requires SpliceAI 0.1 or lower for intronic variants
Sources
cspec ↗spliceai ↗
BP7 This intronic deletion does not meet BP7 because benign splicing evidence was not identified and BP4 is not met; SpliceAI predicts splice impact with a maximum delta score of 0.66 rather than the no-impact profile required for BP7 application. Details ▾Hide ▴
Rule
ENIGMA BP7 RNA/benign splicing rule
Evidence considered
  • SpliceAI max delta score 0.66
  • BP7 for intronic variants requires a benign splicing context and BP4 support
Sources
cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.66).

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 (4 clinical laboratories) and as Pathogenic (3 clinical laboratories) and as 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 = 0.66).

Somatic

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