Final classification

Likely Benign

PP3BS3BP6

BRCA1

c.301+7G>A

p.?

This variant

The BRCA1 c.301+7G>A (NP_009225.1:p.?) variant has been reported in ClinVar and is classified there as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

Transcript

NM_007294.3

HGVS · transcript:coding

NM_007294.3:c.301+7G>A

GRCh38

chr17:43104861 C>T

GRCh37

chr17:41256878 C>T

Official ClinGen ENIGMA BRCA1/BRCA2 final-classification framework used: Specification v1.2 Table 3 with the ENIGMA conflicting-evidence point system.

Classification rationale

PP3 BS3BP6 Likely Benign

BRCA1 c.301+7G>A

The BRCA1 c.301+7G>A (NP_009225.1:p.?) variant has been reported in ClinVar and is classified there as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.¹ This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at AF 5.40093e-05 (87/1610834 alleles; 0 homozygotes), so it is not absent from population controls.² Functional evidence supports a benign effect: ENIGMA BRCA1 Table 9 assigns BS3_Strong for this variant, and RNA studies reported no aberrant splicing.³ Computational splicing evidence predicts possible splice impact, with a SpliceAI maximum delta score of 0.29, which meets the ENIGMA BRCA1 PP3 threshold and does not meet the BP4 threshold.⁴

PP3 + BS3 + BP6 → Likely Benign

1 clinvar ↗cspec ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗

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_007294.3 · variants mapped to exon structure

BRCA1 NM_007294.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 15 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 · 3

Strength Supporting Moderate Strong Very strong

PP3 supporting Pathogenic

SpliceAI predicts splice impact with a maximum delta score of 0.29, which is above the ENIGMA BRCA1 PP3 threshold of 0.2 for intronic variants outside the ±1,2 splice positions. This supports PP3 at supporting strength.

SpliceAI DS_AG 0.21DS_DG 0.29max delta score 0.29.

cspec ↗spliceai ↗

BS3 strong Benign

ENIGMA BRCA1 Table 9 assigns BS3 at strong strength for this variant. A calibrated functional study found function similar to benign control variants, and two RNA studies reported no aberrant splicing, supporting no damaging functional effect.

ENIGMA Table 9: BRCA1 c.301+7G>A = BS3 Strong.ST3: Steffensen 2014 (PMID 24667779) no aberration.ST3: Houdayer 2012 (PMID 22505045) no aberration.

PMID:22505045 ↗PMID:24667779 ↗

BP6 supporting Benign

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

BP6 is listed as not applicable for this VCEP.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 5 not met · 10 not assessed

Pathogenic

PVS1 This intronic BRCA1 variant is at c.301+7, outside the canonical donor ±1,2 positions used for default PVS1 application, and available RNA studies reported no aberrant splicing.

PS1 No qualifying pathogenic reference variant with the same established splicing consequence was identified for this variant, so PS1 was not assessed.

PS3 Available functional evidence does not show a damaging effect.

PS4 No case-control evidence showing significant enrichment in affected individuals was identified, so PS4 was not assessed.

PM2 This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 at AF 5.40093e-05 (87/1610834 alleles; 0 homozygotes) with grpmax FAF 5.311e-05, so it is not absent from population controls and PM2 is not met.

PM3 No evidence was identified for BRCA1-related Fanconi anemia with this variant observed in trans with another BRCA1 variant, so PM3 was not assessed.

PP1 No quantitative segregation data were identified for this variant, so PP1 was not assessed.

PP4 No exact variant-level clinical-history likelihood ratio meeting ENIGMA BRCA1 PP4 thresholds was identified, so PP4 was not assessed.

Benign

BA1 The observed gnomAD v4.1 grpmax FAF is 5.311e-05, which is below the ENIGMA BRCA1 BA1 threshold of 0.001.

BS1 Available population data show that this variant is present at low frequency in gnomAD v4.1, but the reviewed evidence did not establish a clearly qualifying non-founder filter allele frequency for separate BS1 application under the ENIGMA BRCA1 population framework.

BS2 No data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia at the point thresholds required for BS2, so BS2 was not assessed.

BS4 No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed.

BP4 For intronic variants outside the native donor and acceptor ±1,2 positions, ENIGMA BRCA1 requires SpliceAI 0.1 or less for BP4.

BP5 No exact variant-level clinical-history likelihood ratio meeting ENIGMA BRCA1 BP5 thresholds was identified, so BP5 was not assessed.

BP7 This variant is at +7, a position that can enter the ENIGMA BRCA1 BP7 framework, but BP4 is not met because SpliceAI is 0.29.

N/A · 10 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.40093e-05; MAF= 0.00540%, 87/1610834 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000135199; MAF= 0.01352%, 4/29586 alleles, homozygotes = 0); grpmax FAF= 5.311e-05.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0054% · 87 / 1,610,834
0 hom · FAF 0.0053%

Ashkenazi Jewish 4 / 29,586	0.014%
European (non-Finnish) 77 / 1,177,260	0.0065%
Remaining individuals 3 / 62,376	0.0048%
European (Finnish) 3 / 63,922	0.0047%

+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, African/African American)

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 Benign (11 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign 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 = 0.29).

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

2papers cited

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

Guidelines for splicing analysis in molecular diagnosis derived from a set of 32

PMID 22505045 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 strong

Functional characterization of BRCA1 gene variants by mini-gene splicing assay.

PMID 24667779 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 strong

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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