Starting

Initialising…

BRCA2

Final classification

Uncertain Significance

BRCA2 c.2259T>C · p.Phe753=

BRCA2

The BRCA2 c.2259T>C (p.Phe753=) variant has been reported in ClinVar with only likely benign submissions.

Gene

BRCA2

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.2259T>C

Consequence

N/A

GRCh38

chr13:32336614 T>C

GRCh37

chr13:32910751 T>C

Basis ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules via final_classification_framework) ▾

ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules via final_classification_framework)

Classification rationale

BP1 Uncertain Significance

BRCA2 c.2259T>C

The BRCA2 c.2259T>C (p.Phe753=) variant has been reported in ClinVar with only likely benign submissions.¹ This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 3/1614118 alleles (AF 1.8586e-06; grpmax FAF 6.8e-07), which is far below ENIGMA BRCA2 BA1 and BS1 thresholds but does not satisfy absence from controls for PM2.² SpliceAI predicts no meaningful splice effect for this synonymous change (max delta score 0.00), and codon 753 lies outside the ENIGMA-defined BRCA2 clinically important domains, supporting BP1_Strong and not supporting PP3 or PVS1.³

BP1 → Uncertain Significance

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗vcep_specifications_v1_2_2024_11_18

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

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

This variant is present in gnomAD v4.1 (AF= 1.8586e-06; MAF= 0.00019%, 3/1614118 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54237e-06; MAF= 0.00025%, 3/1180000 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,614,118
0 hom · FAF 6.8e-05%

European (non-Finnish)

3 / 1,180,000

0.00025%

+ 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 benign (4 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 516910)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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