Variant classification summary

NM_000059.4:c.9117G>A

BRCA2 · NP_000050.3:p.(Pro3039=) · NM_000059.4

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

Gene: BRCA2 Transcript: NM_000059.4

Final call

VUS

PP3 PP4 PP5

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Pro3039=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.9117G>A (p.(Pro3039=), p.(P3039=)) variant has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification from the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.

2

This variant is rare in population databases but is not absent from controls, with 1/248378 alleles in gnomAD v2.1 (AF 0.00000403) and 6/1613032 alleles in gnomAD v4.1 (AF 0.00000372), so PM2 is not met and BA1/BS1 thresholds are not reached.

3

Clinical-history likelihood-ratio analysis for BRCA2 c.9117G>A showed LR 3.91 in 12 probands, which exceeds the ENIGMA PP4 supporting threshold of 2.08 and supports PP4 at supporting strength.

4

SpliceAI predicts a strong splice effect for this synonymous variant, with a maximum delta score of 0.89, which is above the ENIGMA PP3 threshold of 0.20 for predicted splicing impact and argues against BP4/BP7.

Final determination: Three supporting pathogenic criteria (PP3, PP4, and PP5) do not reach an ENIGMA BRCA1/2 Table 3 combination for likely pathogenic or pathogenic classification; in the absence of a qualifying benign combination, the variant is classified as uncertain significance.

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 synonymous variant does not fall into the default null-variant categories for PVS1, and no direct mRNA assay evidence was identified here to show a proven loss-of-function transcript effect. Predicted splice impact alone does not satisfy BRCA2 PVS1 without supporting RNA data.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No same-amino-acid-change comparator or same proven splice-effect pathogenic comparator was identified here for this variant, so PS1 was not applied.	cspec
PS2	N/A	De novo evidence is not used for BRCA2 in this framework, so PS2 is not applicable.	cspec
PS3	Not assessed	No calibrated protein functional assay result for BRCA2 c.9117G>A was identified in the reviewed BRCA2 functional table, so PS3 was not applied.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	This variant has been reported in affected individuals and is listed as pathogenic in expert-curated resources, but no case-control analysis meeting the BRCA2 PS4 rule was identified here. PS4 was therefore not applied in this pass.	clinvar cspec vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	PM1 is not applicable in the BRCA2 ENIGMA framework.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/248378 alleles (AF 0.00000403) and in gnomAD v4.1 at 6/1613032 alleles (AF 0.00000372), so the ENIGMA BRCA2 PM2 absence criterion is not met.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not applied.	cspec
PM4	N/A	PM4 is not applicable in the BRCA2 ENIGMA framework.	cspec
PM5	N/A	In this framework PM5 is used for protein-termination-codon variants in eligible exons, and this variant is a synonymous substitution rather than a protein-truncating variant.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not applicable in the BRCA2 ENIGMA framework.	cspec
PP1	Not assessed	No quantitative co-segregation likelihood ratio was identified for this variant, so PP1 was not applied.	cspec
PP2	N/A	PP2 is not applicable in the BRCA2 ENIGMA framework.	cspec
PP3	Met	SpliceAI predicts a strong splice effect for this synonymous variant, with a maximum delta score of 0.89, which is above the BRCA2 ENIGMA PP3 threshold of 0.20 for predicted splicing impact. This supports PP3 at supporting strength.	spliceai cspec
PP4	Met	Clinical-history likelihood-ratio analysis for BRCA2 c.9117G>A showed LR 3.91 in 12 probands, which is above the ENIGMA PP4 supporting threshold of 2.08 and below the moderate threshold of 4.3. This supports PP4 at supporting strength.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	The observed population frequency is well below the ENIGMA BA1 threshold. In gnomAD v4.1 the highest filter allele frequency was 0.00000183, which is below the BA1 threshold of 0.001, so BA1 is not met.	gnomad_v4 cspec
BS1	Not met	The observed population frequency does not reach the ENIGMA BS1 thresholds. In gnomAD v4.1 the highest filter allele frequency was 0.00000183, which is below the supporting threshold of 0.00002 and below the strong threshold of 0.0001, so BS1 is not met.	gnomad_v4 cspec
BS2	Not assessed	No point-based evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia as required by the BRCA2 ENIGMA BS2 rule, so BS2 was not applied.	cspec
BS3	Not assessed	No calibrated benign functional assay result for BRCA2 c.9117G>A was identified in the reviewed BRCA2 functional table, so BS3 was not applied.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation likelihood ratio was identified for this variant, so BS4 was not applied.	cspec
BP1	Not met	This synonymous variant lies within the BRCA2 DNA-binding region (amino acids 2481-3186), and SpliceAI predicts splice impact with a maximum delta score of 0.89. BP1_Strong requires a silent or missense/in-frame variant outside a clinically important domain and no predicted splice impact (SpliceAI ≤0.10), so BP1 is not met.	cspec spliceai
BP2	N/A	BP2 is not applicable in the BRCA2 ENIGMA framework.	cspec
BP3	N/A	BP3 is not applicable in the BRCA2 ENIGMA framework.	cspec
BP4	Not met	For a silent variant in a clinically important BRCA2 domain, BP4 requires no predicted splice impact with SpliceAI at or below 0.10. This variant has a SpliceAI maximum delta score of 0.89, which is above that threshold, so BP4 is not met.	spliceai cspec
BP5	Not met	Clinical-history likelihood-ratio analysis for BRCA2 c.9117G>A showed LR 3.91 in 12 probands, which is above the benign BP5 threshold of 0.48 and therefore does not support BP5. The value is in the pathogenic rather than benign direction.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
BP6	N/A	BP6 is not applicable in the BRCA2 ENIGMA framework.	cspec
BP7	Not met	This is a silent variant within the BRCA2 DNA-binding domain, but BP7 for this setting requires BP4 to be met, and BP4 is not met because SpliceAI predicts strong splice impact with a maximum delta score of 0.89. No benign RNA assay evidence was identified for BP7(RNA).	spliceai cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.