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

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_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 17 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

BP1 strong review Benign

This is a synonymous BRCA2 variant outside the ENIGMA-defined clinically important domains, and SpliceAI predicts no splice effect (max delta score 0.00, below the <=0.1 threshold), which meets BP1_Strong.

Protein consequence is p.(Phe753=).ENIGMA clinically important BRCA2 domains are aa 10-40 and aa 2481-3186codon 753 is outside these regions.

cspec ↗spliceai ↗

Assessed · not applied · 6 not met · 11 not assessed

Pathogenic

PVS1 This synonymous variant does not fall within the BRCA2 null-variant or canonical splice-site categories used for PVS1, and SpliceAI predicts no splice disruption (max delta score 0.00), so available evidence does not support a loss-of-function effect for this criterion.

PS1 No evidence was identified that this variant produces the same proven pathogenic protein or splice consequence as a previously classified pathogenic or likely pathogenic BRCA2 variant, so PS1 was not assessed.

PS3 No calibrated BRCA2 functional assay result for this exact variant was identified in the reviewed BRCA2 functional datasets, so PS3 was not assessed.

PS4 No case-control study or quantitative enrichment data showing a significant excess of this variant in affected individuals was identified, so PS4 was not assessed.

PM2 This variant is not absent from controls because it is present in gnomAD v4.1 at 3/1,614,118 alleles (AF 1.8586e-06; grpmax FAF 6.8e-07), so available population data do not support PM2.

PM3 No evidence was identified that this variant was observed in trans with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed.

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

PP3 SpliceAI predicts no meaningful splice effect for this synonymous variant (max delta score 0.00), which is below the ENIGMA BRCA2 PP3 splice threshold of 0.2, so PP3 is not met.

PP4 No exact match for this variant was identified in the BRCA2 clinical-history likelihood-ratio table, so there is no quantitative multifactorial clinical-history evidence to support PP4 at this time.

Benign

BA1 The observed gnomAD v4.1 grpmax FAF is 6.8e-07, which is well below the ENIGMA BRCA2 BA1 threshold of greater than 0.001, so BA1 is not met.

BS1 The observed gnomAD v4.1 grpmax FAF is 6.8e-07, which is below both the ENIGMA BRCA2 BS1 Supporting threshold of greater than 0.00002 and the Strong threshold of greater than 0.0001, so BS1 is not met.

BS2 No evidence was identified that this variant was observed under the ENIGMA BRCA2 unaffected or non-Fanconi-anemia conditions required for BS2 point assignment, so BS2 was not assessed.

BS3 No calibrated BRCA2 functional or RNA assay demonstrating no damaging effect for this exact variant was identified, so BS3 was not assessed.

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

BP4 SpliceAI predicts no splice effect (max delta score 0.00), but the ENIGMA BRCA2 BP4 rule for silent variants is limited to synonymous variants inside clinically important domains; this variant is at codon 753, outside those domains, so BP4 is not met.

BP5 No exact match for this variant was identified in the BRCA2 clinical-history likelihood-ratio table, so there is no quantitative multifactorial clinical-history evidence to support BP5 at this time.

BP7 SpliceAI predicts no splice effect (max delta score 0.00), but no variant-specific RNA study showing normal transcript processing was identified, and this outside-domain synonymous variant does not meet the ENIGMA BP7 supporting rule that is limited to silent variants inside clinically important domains with BP4 met.

N/A · 10 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6

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

Check your email

Reset your password

Enter an access code

Your allowance