Starting

Initialising…

BRCA1

Final classification

uncertain_significance

BRCA1 c.80+5G>C · p.?

BRCA1

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.

Gene

BRCA1

Transcript

NM_007294.4

HGVS · transcript:coding

NM_007294.4:c.80+5G>C

Consequence

N/A

GRCh38

chr17:43124012 C>G

GRCh37

chr17:41276029 C>G

Basis ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 criteria-combination framework (official CSPEC/VCEP final-classification framework override) ▾

ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 criteria-combination framework (official CSPEC/VCEP final-classification framework override)

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 ↗

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

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 1 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

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