Classification rationale

BA1BS1BP4BP7 Benign

BRCA2 c.682-30A>C

The BRCA2 c.682-30A>C (p.?) variant has been reported in ClinVar as benign by 2 clinical laboratories and likely benign by 2 clinical laboratories.¹ This variant is present in gnomAD with a group maximum filter allele frequency of 0.00539635 in v2.1 and 0.00494792 in v4.1, both above the ENIGMA BRCA2 BA1 threshold of 0.001 and the BS1 strong threshold of 0.0001.² SpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.01, which supports BP4 and BP7 under the ENIGMA BRCA2 splicing rules.³

BA1 + BS1 + BP4 + BP7 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

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_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 13 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 · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This variant is too common for a pathogenic BRCA2 variant under the ENIGMA population rule. The gnomAD group maximum filter allele frequency is 0.00539635 in v2.1 and 0.00494792 in v4.1, both above the BA1 threshold of 0.001, so BA1 is met.

gnomAD v2.1 grpmax FAF 0.00539635.gnomAD v4.1 grpmax FAF 0.00494792.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 strong Benign

This variant exceeds the ENIGMA BRCA2 BS1 strong threshold for population frequency. The gnomAD group maximum filter allele frequency is 0.00539635 in v2.1 and 0.00494792 in v4.1, both above the BS1 strong threshold of 0.0001.

gnomAD v2.1 grpmax FAF 0.00539635.gnomAD v4.1 grpmax FAF 0.00494792.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP4 supporting Benign

This intronic variant lies outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the ENIGMA BRCA2 BP4 threshold of 0.10. BP4 is met.

Variant position c.682-30 is outside +/-12 splice sites.SpliceAI max delta score 0.01.

spliceai ↗cspec ↗

BP7 supporting Benign

This intronic variant is located at c.682-30, which is beyond the ENIGMA BRCA2 intronic BP7 boundary of -21, and BP4 is satisfied because SpliceAI predicts no significant splice effect with a maximum delta score of 0.01. BP7 is met.

Variant position c.682-30 is beyond -21.SpliceAI max delta score 0.01.BP4 criteria are satisfied.

spliceai ↗cspec ↗

Assessed · not applied · 3 not met · 10 not assessed

Pathogenic

PVS1 This intronic variant is not a canonical +/-1,2 splice-site variant, and no damaging mRNA assay result was identified to support RNA-based PVS1.

PS1 No previously classified pathogenic or likely pathogenic variant with the same established splice effect was identified from the reviewed evidence, so PS1 was not applied.

PS3 No well-established functional study showing a damaging effect for this specific variant was identified, and no variant-level PS3 assignment was found in the reviewed BRCA2 functional resources.

PS4 No case-control evidence or quantitative enrichment data meeting the ENIGMA BRCA2 PS4 threshold were identified for this variant, so PS4 was not applied.

PM2 This variant is not absent from population databases.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not applied.

PP1 No quantitative co-segregation evidence was identified for this variant, so PP1 was not applied.

PP3 SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.01, which is below the ENIGMA BRCA2 PP3 threshold of 0.20.

PP4 No variant-level multifactorial clinical-history likelihood ratio meeting the ENIGMA BRCA2 PP4 thresholds was identified for this variant, so PP4 was not applied.

Benign

BS2 Although this variant has been observed in population databases, no qualifying BRCA2-related Fanconi anemia point-based evidence was identified to apply BS2 under the ENIGMA BRCA2 framework.

BS3 No well-established functional study showing no damaging effect for this specific variant was identified, and no variant-level BS3 assignment was found in the reviewed BRCA2 functional resources.

BS4 No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not applied.

BP5 No variant-level multifactorial clinical-history likelihood ratio meeting the ENIGMA BRCA2 BP5 thresholds was identified for this variant, so BP5 was not applied.

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

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000289734; MAF= 0.02897%, 391/1349516 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00539895; MAF= 0.53989%, 375/69458 alleles, homozygotes = 1); grpmax FAF= 0.00494792.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000536223; MAF= 0.05362%, 136/253626 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.0060639; MAF= 0.60639%, 134/22098 alleles, homozygotes = 1); grpmax FAF= 0.00539635.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.029% · 391 / 1,349,516
1 hom · FAF 0.49%

African/African American 375 / 69,458	0.54% 1 hom
Remaining individuals 10 / 53,468	0.019%
Admixed American 5 / 57,824	0.0086%
European (non-Finnish) 1 / 945,462	0.00011%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.054% · 136 / 253,626
1 hom · FAF 0.54%

African/African American 134 / 22,098	0.61% 1 hom
Admixed American 2 / 33,220	0.006%

+ 6 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (2 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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