Variant classification summary

NM_000059.3:c.9234C>T

BRCA2 · NP_000050.2:p.(Val3078=) · NM_000059.3

GRCh37: chr13:32954260 C>T · GRCh38: chr13:32380123 C>T

Gene: BRCA2 Transcript: NM_000059.3

Final call

Likely Benign

BP4_Supporting BP5_Supporting BP6_Supporting BP7_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Val3078=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.9234C>T (p.Val3078=; p.V3078=) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1/BRCA2 expert panel.

2

This variant is present at low frequency in gnomAD, with AF 1.77e-05 in v2.1 and AF 2.11e-05 in v4.1; these frequencies are above the ENIGMA PM2 absence-from-controls requirement and below the BS1 and BA1 frequency thresholds.

3

In the BRCA2 clinical-history likelihood-ratio dataset, this variant has an LR of 0.284 from 12 probands, which is in the benign direction and meets ENIGMA BP5 at Supporting strength.

4

Computational splice prediction does not support splice disruption: SpliceAI shows a maximum delta score of 0.06, below the ENIGMA BP4/BP7 threshold of 0.1 and below the PP3 splice threshold of 0.2.

Final determination: Likely Benign based on at least two Supporting benign criteria under ENIGMA BRCA1/BRCA2 Table 3; here BP4_Supporting, BP5_Supporting, BP6_Supporting, and BP7_Supporting are met.

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 create a protein-truncating change and is not a canonical ±1,2 splice-site variant, so the BRCA2 PVS1 loss-of-function rule is not met.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No pathogenic or likely pathogenic reference variant with the same established splice effect was identified, so PS1 was not assessed from the available evidence.	cspec spliceai
PS2	N/A	De novo occurrence criteria are not applicable in this BRCA2 ENIGMA framework.	cspec
PS3	Not assessed	This variant was not identified in the reviewed ENIGMA functional assay resources, and no calibrated damaging functional study for this exact variant was established from the available evidence.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PS4	Not assessed	No case-control enrichment data or quantitative multifactorial evidence meeting ENIGMA PS4 thresholds were identified for this exact variant.	vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PM1	N/A	PM1 is not applicable in this BRCA2 ENIGMA framework.	cspec
PM2	Not met	This variant is present in population databases, so the ENIGMA PM2 absence-from-controls rule is not met. It is seen in gnomAD v2.1 at AF 1.77e-05 (5/282222; grpmax FAF 7.02e-06) and in gnomAD v4.1 at AF 2.11e-05 (34/1613428; grpmax FAF 1.963e-05).	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified for biallelic BRCA2 disease context or a quantified Fanconi-anemia-related observation that would allow PM3 assessment.	cspec
PM4	N/A	PM4 is not applicable in this BRCA2 ENIGMA framework.	cspec
PM5	N/A	This is a synonymous variant and not a protein termination codon variant, so the BRCA2 PM5/PTC rule does not apply.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not applicable in this BRCA2 ENIGMA framework.	cspec
PP1	Not assessed	No quantitative cosegregation analysis or family-based segregation evidence meeting ENIGMA thresholds was identified for this variant.	cspec
PP2	N/A	PP2 is not applicable in this BRCA2 ENIGMA framework.	cspec
PP3	Not met	Available computational evidence does not support a splice-disrupting effect. SpliceAI shows a maximum delta score of 0.06, which is below the ENIGMA PP3 splice threshold of 0.2. No REVEL or BayesDel score was available or relevant to support PP3 for this synonymous variant.	spliceai cspec
PP4	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 0.284 from 12 probands, which is below the ENIGMA PP4 pathogenic threshold of 2.08 and therefore does not support PP4.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
PP5	N/A	PP5 is not applicable in this BRCA2 ENIGMA framework.	cspec
BA1	Not met	Population frequency does not reach the ENIGMA BA1 stand-alone benign threshold. The highest observed FAF is 1.963e-05 in gnomAD v4.1, which is well below the BA1 threshold of 0.001.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Population frequency does not reach the ENIGMA BS1 threshold. The highest observed FAF is 1.963e-05 in gnomAD v4.1, which is below the BS1 Supporting threshold of 2e-05 and below the BS1 Strong threshold of 1e-04.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No qualifying phenotype-based evidence was identified to assess BS2 under the BRCA2 Fanconi-anemia-focused ENIGMA rule.	cspec
BS3	Not assessed	This variant was not identified in the reviewed ENIGMA functional assay resources, and no calibrated benign functional study for this exact variant was established from the available evidence.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
BS4	Not assessed	No quantitative nonsegregation evidence or benign multifactorial likelihood ratio meeting ENIGMA BS4 thresholds was identified for this exact variant.	vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
BP1	Not met	This synonymous variant is located at codon 3078, which falls within the BRCA2 DNA-binding region defined by ENIGMA as aa 2481-3186, so the outside-domain BP1 rule is not met even though no splice effect is predicted.	cspec spliceai
BP2	N/A	BP2 is not applicable in this BRCA2 ENIGMA framework.	cspec
BP3	N/A	BP3 is not applicable in this BRCA2 ENIGMA framework.	cspec
BP4	Met	This is a silent BRCA2 variant within the DNA-binding region, and computational splicing evidence does not predict a meaningful splice effect. SpliceAI shows a maximum delta score of 0.06, which is below the ENIGMA BP4 threshold of 0.1, so BP4 is met at Supporting strength.	cspec spliceai
BP5	Met	Clinical-history evidence is in the benign direction. The BRCA2 clinical-history likelihood ratio for this variant is 0.284 from 12 probands, which is at or below the ENIGMA BP5 Supporting threshold of 0.48 and above the BP5 Moderate threshold of 0.23, so BP5 is met at Supporting strength.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
BP6	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	Met	This is a silent variant within a clinically important BRCA2 domain, and BP4 is met because SpliceAI predicts no significant splice impact (maximum delta score 0.06, below the 0.1 threshold). Under the ENIGMA rule for silent variants in clinically important domains, this supports BP7 at Supporting strength.	cspec spliceai

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