Variant classification summary

NM_000059.3:c.9117G>A

BRCA2 · NP_000050.2:p.(Pro3039=) · NM_000059.3

GRCh37: chr13:32954050 G>A · GRCh38: chr13:32379913 G>A

Gene: BRCA2 Transcript: NM_000059.3

Final call

Pathogenic

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Pro3039=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.9117G>A (p.Pro3039=) variant has been reported in ClinVar as Pathogenic with expert panel review.

2

This variant is rare in population databases, with AF 4.03e-06 (1/248378 alleles) in gnomAD v2.1 and AF 3.72e-06 (6/1613038 alleles) in gnomAD v4.1.

3

In a published RNA study, this variant caused exon 23 skipping in puromycin-treated lymphocytes, supporting an abnormal splicing effect consistent with loss of function.

4

SpliceAI predicts strong splice disruption with a maximum delta score of 0.89, which supports a deleterious splicing effect.

5

In the BRCA2-specific clinical-history likelihood dataset, this variant had an LR of 3.91 in 12 probands, meeting ENIGMA PP4 at supporting strength.

Final determination: PVS1 at very strong strength together with at least two supporting pathogenic criteria meets the ENIGMA BRCA2 Table 3 rule for a pathogenic classification.

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	Met	This synonymous variant affects the last nucleotide of exon 23. In a published RNA study using puromycin-treated lymphocytes, this variant caused exon 23 skipping. Exon 23 is 164 nucleotides long, so complete skipping is out of frame, and ENIGMA Table 4 assigns exon 23 loss/spliceogenic RNA events to PVS1/PVS1(RNA). Because BRCA2 loss of function is an established disease mechanism, this supports PVS1 at very strong strength.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pmid_22505045_houdayer_2012_hummutat vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS1	Not assessed	Available evidence confirms abnormal splicing for this variant, but the reviewed materials do not establish a same-effect reference pathogenic variant under the ENIGMA PS1 splicing framework strongly enough to assign PS1 here.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS2	N/A	ENIGMA BRCA2 v1.2 marks PS2 as not applicable in this framework.	cspec
PS3	Not assessed	RNA studies showed exon 23 skipping, but ENIGMA directs mRNA-only damaging evidence to PVS1(RNA) rather than PS3. No qualifying protein-based or combined protein-plus-RNA functional study was identified for separate PS3 assignment.	cspec vcep_pmid_22505045_houdayer_2012_hummutat vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	This variant has been reported in affected individuals and appears in the ENIGMA reference-set materials with a very high posterior probability, but the reviewed materials do not provide a qualifying case-control odds ratio and p-value meeting the ENIGMA PS4 rule. PS4 was therefore not independently assigned here.	clinvar vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PM1	N/A	ENIGMA BRCA2 v1.2 marks PM1 as not applicable in this framework.	cspec
PM2	Not met	This variant is not absent from controls. It is present in gnomAD v2.1 at 1/248378 alleles (AF 4.03e-06) and in gnomAD v4.1 at 6/1613038 alleles (AF 3.72e-06), so the ENIGMA PM2 absence requirement is not met.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia, so PM3 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	ENIGMA BRCA2 v1.2 marks PM4 as not applicable in this framework.	cspec
PM5	N/A	PM5 in this framework applies to missense substitutions at the same residue or to eligible protein-termination codon events. This variant is synonymous and is not a protein-termination codon variant, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PM6	N/A	ENIGMA BRCA2 v1.2 marks PM6 as not applicable in this framework.	cspec
PP1	Not assessed	No quantitative co-segregation likelihood ratio for this exact variant was identified in the reviewed materials, so PP1 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PP2	N/A	ENIGMA BRCA2 v1.2 marks PP2 as not applicable in this framework.	cspec
PP3	Met	Computational splicing evidence supports a deleterious splice effect. SpliceAI predicts strong splice disruption with a maximum delta score of 0.89, which is above the ENIGMA PP3 threshold of 0.2 for predicted splicing impact in silent variants.	cspec spliceai vcep_specifications_v1_2_2024_11_18
PP4	Met	Clinical-history likelihood analysis supports pathogenicity. In the BRCA2-specific Li et al. dataset, this variant had an LR of 3.91 in 12 probands, which is above the ENIGMA PP4 Supporting threshold of 2.08 and below the Moderate threshold of 4.3.	PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr vcep_specifications_v1_2_2024_11_18
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	Population frequency does not meet the ENIGMA BA1 threshold. The highest reviewed frequency is 3.72e-06 in gnomAD v4.1, which is far below the BA1 cutoff of 0.001.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS1	Not met	Population frequency does not meet the ENIGMA BS1 threshold. The highest reviewed frequency is 3.72e-06 in gnomAD v4.1, which is below the BS1 Supporting threshold of 0.00002 and far below the Strong threshold of 0.0001.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS2	Not assessed	No informative evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia at a level that would satisfy the ENIGMA BS2 point-based framework.	cspec vcep_specifications_v1_2_2024_11_18
BS3	Not met	Available functional evidence does not support a benign effect. Instead, RNA studies showed exon 23 skipping, which is consistent with an abnormal splicing effect rather than no damaging effect.	vcep_pmid_22505045_houdayer_2012_hummutat vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation likelihood ratio for this exact variant was identified in the reviewed materials, so BS4 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
BP1	Not met	This silent variant does not meet ENIGMA BP1_Strong because predicted splice impact is present. SpliceAI is 0.89, which is above the no-splicing-impact threshold of 0.1.	cspec spliceai vcep_specifications_v1_2_2024_11_18
BP2	N/A	ENIGMA BRCA2 v1.2 marks BP2 as not applicable in this framework.	cspec
BP3	N/A	ENIGMA BRCA2 v1.2 marks BP3 as not applicable in this framework.	cspec
BP4	Not met	This silent variant does not meet BP4 because ENIGMA requires no predicted splice impact for a silent variant in a clinically important functional domain, with SpliceAI at or below 0.1. The observed SpliceAI maximum delta score is 0.89, which is above that threshold.	cspec spliceai vcep_specifications_v1_2_2024_11_18
BP5	Not met	Clinical-history likelihood analysis does not support a benign interpretation. The variant-level LR is 3.91 in 12 probands, which is above the benign BP5 threshold of 0.48 rather than at or below it.	PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr vcep_specifications_v1_2_2024_11_18
BP6	N/A	ENIGMA BRCA2 v1.2 marks BP6 as not applicable in this framework.	cspec
BP7	Not met	This silent variant does not meet BP7. ENIGMA requires either BP4 for silent variants in a clinically important functional domain or RNA evidence showing no damaging transcript effect. Here, SpliceAI is 0.89 and published RNA studies showed exon 23 skipping, so the evidence argues against BP7.	cspec spliceai vcep_pmid_22505045_houdayer_2012_hummutat vcep_specifications_v1_2_2024_11_18

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