Starting

Initialising…

BRCA1

Final classification

Likely Pathogenic

BRCA1 c.442-22_442-13del · p.?

BRCA1

Gene

BRCA1

Transcript

NM_007294.4

HGVS · transcript:coding

NM_007294.4:c.442-22_442-13del

Consequence

N/A

GRCh38

chr17:43099892 GGTAAAGAACA>G

GRCh37

chr17:41251909 GGTAAAGAACA>G

Basis 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. ▾

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.

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 ↗

Gene diagram · NM_007294.4 · variants mapped to exon structure

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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.

PMID PMID:10323242

PMID PMID:10323242 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 supports · met

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC