Classification rationale

BP4 uncertain_significance

BRCA1 c.80+5G>C

The BRCA1 c.80+5G>C (NP_009225.1:p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance without expert panel review.¹ This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which supports rarity in population databases.² SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the BRCA1 PP3 threshold of 0.2 and within the BP4 no-splice-impact threshold of 0.1 for intronic variants outside the native donor ±1,2 positions.³

BP4 → uncertain_significance

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 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 · 1 applied · 16 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 · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

This intronic variant lies outside the native donor ±1,2 splice positions, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. This is below the BRCA1 BP4 threshold of 0.1 for no predicted splice impact, so BP4 is met at Supporting strength.

Variant location is c.80+5.SpliceAI max delta score = 0.00which is ≤0.1.

spliceai ↗cspec ↗

Assessed · not applied · 6 not met · 10 not assessed

Pathogenic

PVS1 This intronic variant is at donor position +5, not at the canonical ±1,2 splice site positions used for BRCA1 PVS1 application, and no variant-specific RNA study showing an abnormal transcript with loss-of-function consequence was identified.

PS1 No previously classified pathogenic or likely pathogenic variant with the same demonstrated splice effect as this variant was identified.

PS3 No calibrated functional study for c.80+5G>C was identified in the reviewed BRCA1 functional tables.

PS4 No case-control or statistically enriched affected-individual data were identified for this variant.

PM2 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity.

PM3 No evidence was identified that this variant has been observed in trans with another BRCA1 pathogenic variant in a person with BRCA1-related Fanconi anemia.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed.

PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.

PP4 No exact clinical-history likelihood-ratio entry for c.80+5G>C was identified in the reviewed BRCA1 clinical-history dataset, so PP4 cannot be assessed from the available evidence.

Benign

BA1 This variant is absent from the reviewed population datasets and therefore is well below the BRCA1 BA1 threshold of filter allele frequency greater than 0.1%.

BS1 This variant is absent from the reviewed population datasets and therefore is below the BRCA1 BS1 thresholds of filter allele frequency greater than 0.002% or 0.01%.

BS2 No point-based evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia as required by the BRCA1 ENIGMA framework.

BS3 No well-established functional study showing normal splicing or normal BRCA1 function for c.80+5G>C was identified.

BS4 No lack-of-segregation data were identified for this variant, so BS4 cannot be assessed.

BP5 No exact clinical-history likelihood-ratio entry for c.80+5G>C was identified in the reviewed BRCA1 clinical-history dataset, so BP5 cannot be assessed from the available evidence.

BP7 SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BRCA1 BP7_Supporting for intronic variants is limited to positions at or beyond +7 or -21 when BP4 is met.

N/A · 11 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 433683)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 9 PMIDs not cited in assessment

17576681 ↗ Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. CLINVAR

23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. CLINVAR

9536098 ↗ Statistical features of human exons and their flanking regions. CLINVAR

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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