Starting

Initialising…

BRCA2

Final classification

Likely Pathogenic

BRCA2 c.6859A>T · p.Arg2287Ter

BRCA2

The BRCA2 c.6859A>T (p.Arg2287Ter; p.R2287*) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic with expert panel review.

Gene

BRCA2

Transcript

NM_000059.3

HGVS · transcript:coding

NM_000059.3:c.6859A>T

Consequence

N/A

GRCh38

chr13:32344575 A>T

GRCh37

chr13:32918712 A>T

Basis ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP override) applied to the authoritative adjudicated criteria. ▾

ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP override) applied to the authoritative adjudicated criteria.

Classification rationale

PVS1PP5 Likely Pathogenic

BRCA2 c.6859A>T

The BRCA2 c.6859A>T (p.Arg2287Ter; p.R2287*) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic with expert panel review.¹ This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1,556,108 alleles; AF 6.43e-07; no homozygotes), consistent with extreme rarity.² Under the ENIGMA BRCA2 specification, this exon 12 premature termination variant is a null variant in a gene where loss of function is an established disease mechanism, and the exon-level table assigns PVS1 to protein-truncating variants in exon 12.³ SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, which does not support PP3 for splice disruption.⁴

PVS1 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗vcep_specifications_table4_v1_2_2024_11_18pvs1_gene_contextpvs1_variant_assessment

4 spliceai ↗cspec ↗

Gene diagram · NM_000059.3 · variants mapped to exon structure

BRCA2 NM_000059.3

Fetching transcript structure from UCSC…

Applied criteria · 2 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

This variant is present in gnomAD v4.1 (AF= 6.42629e-07; MAF= 0.00006%, 1/1556108 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84903e-07; MAF= 0.00009%, 1/1130068 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.4e-05% · 1 / 1,556,108
0 hom

European (non-Finnish)

1 / 1,130,068

8.8e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, 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 Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.566539.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots