Variant classification summary

NM_000059.4:c.682-30A>C

BRCA2 · NP_000050.3:p.? · NM_000059.4

GRCh37: chr13:32905026 A>C · GRCh38: chr13:32330889 A>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

Benign

BA1 BS1 BP4 BP7

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

Final determination: Benign because BA1 (stand-alone benign) is met under ENIGMA Table 3; additional benign support is present from BS1, BP4, and BP7.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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. Available evidence therefore does not support applying PVS1 for BRCA2 c.682-30A>C.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	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.	cspec
PS2	N/A	The ENIGMA BRCA2 specification does not use PS2 for this framework.	cspec
PS3	Not assessed	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.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control evidence or quantitative enrichment data meeting the ENIGMA BRCA2 PS4 threshold were identified for this variant, so PS4 was not applied.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	PM1 is not used as a standalone criterion in the ENIGMA BRCA2 framework and is instead captured through the bioinformatic workflow when relevant.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at 136/253626 alleles (AF 0.000536223) and in gnomAD v4.1 at 391/1349516 alleles (AF 0.000289734), so PM2 is not met.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	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.	cspec
PM4	N/A	PM4 is not applicable to this ENIGMA BRCA2 framework.	cspec
PM5	N/A	In the ENIGMA BRCA2 framework, PM5 is used for protein termination codon variants in eligible exons. This intronic c.682-30A>C variant is not a protein termination variant, so PM5 does not apply.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	The ENIGMA BRCA2 specification does not use PM6 for this framework.	cspec
PP1	Not assessed	No quantitative co-segregation evidence was identified for this variant, so PP1 was not applied.	cspec
PP2	N/A	The ENIGMA BRCA2 specification does not use PP2 for this framework.	cspec
PP3	Not met	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. PP3 is therefore not met.	spliceai cspec
PP4	Not assessed	No variant-level multifactorial clinical-history likelihood ratio meeting the ENIGMA BRCA2 PP4 thresholds was identified for this variant, so PP4 was not applied.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not used in the ENIGMA BRCA2 framework.	cspec
BA1	Met	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 gnomad_v4 cspec
BS1	Met	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 gnomad_v4 cspec
BS2	Not assessed	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.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	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.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not applied.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1	N/A	BP1 in the ENIGMA BRCA2 framework is used for silent, missense, or in-frame variants with no predicted splice effect. This intronic variant does not fit that rule, so BP1 is not applicable.	cspec
BP2	N/A	The ENIGMA BRCA2 specification does not use BP2 for this framework.	cspec
BP3	N/A	The ENIGMA BRCA2 specification does not use BP3 as a standalone criterion in this framework.	cspec
BP4	Met	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.	spliceai cspec
BP5	Not assessed	No variant-level multifactorial clinical-history likelihood ratio meeting the ENIGMA BRCA2 BP5 thresholds was identified for this variant, so BP5 was not applied.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	The ENIGMA BRCA2 specification does not use BP6 for this framework.	cspec
BP7	Met	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.	spliceai cspec

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