Classification rationale

PVS1PM2PP3PP5 Likely Pathogenic

BRCA1 c.442-22_442-13del

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.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.² 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.³ 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.⁴

PVS1 + PM2 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 PMID:10323242 ↗PMID:32745242 ↗

4 spliceai ↗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 · 4 applied · 14 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 · 4

Strength Supporting Moderate Strong Very strong

PVS1 strong review Pathogenic

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.

ENIGMA BRCA1/2 VCEP PVS1 RNA framework for non-canonical splice variantsPublished RNA study reporting a 59-nt intron 7 insertion with frameshift and premature termination

cspec ↗PMID:10323242 ↗

PM2 supporting review Pathogenic

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.

gnomAD v2.1 absentgnomAD v4.1 absent

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 supporting review Pathogenic

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.

SpliceAI max delta score 0.66ENIGMA PP3 threshold for predicted splicing impact is at least 0.2

cspec ↗spliceai ↗

PP5 supporting review Pathogenic

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

ENIGMA BRCA1 specification lists PP5 as not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

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.

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.

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.

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.

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.

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.

Benign

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%.

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.

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.

BS3 No well-established functional study showing no damaging effect was identified for this variant, so BS3 is not supported by the available evidence.

BS4 No quantitative evidence showing lack of segregation with disease was identified, so BS4 cannot be applied from the available materials.

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.

BP5 No exact variant-level clinical-history likelihood ratio meeting ENIGMA BP5 benign thresholds was identified in the available structured resources.

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.

N/A · 10 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP1 · BP2 · BP3 · BP6

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

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).

ClinVar ↗

In silico

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

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

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

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Molecular characterization of germline mutations in the BRCA1 and BRCA2 genes fr

PMID 10323242 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 strong

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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