Variant classification summary

NM_000059.4:c.9234C>T

BRCA2 · NP_000050.3:p.(Val3078=) · NM_000059.4

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

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Val3078=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 NM_000059.4:c.9234C>T (p.Val3078=; p.V3078=) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1/2 expert panel.

2

This variant is rare but not absent in population databases, with gnomAD v2.1 AF 1.77165e-05 (5/282222 alleles) and gnomAD v4.1 AF 2.10731e-05 (34/1613428 alleles); the highest observed filter allele frequency is 1.963e-05, which is below the BS1 supporting threshold of greater than 0.00002 and inconsistent with the PM2 requirement for absence.

3

BRCA2 clinical-history likelihood data show an LR of 0.284 in 12 probands, which is at or below the BP5 supporting threshold of 0.48 and supports a benign clinical-history code.

4

This synonymous variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, supporting BP4 and BP7 and arguing against PP3.

Final determination: Four benign supporting criteria are met (BP4, BP5, BP6, and BP7), which satisfies the ENIGMA Table 3 rule for a Likely Benign 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	N/A	This is a synonymous variant, not a nonsense, frameshift, canonical ±1,2 splice-site, initiation-codon, or exon-loss variant, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not met	No evidence was identified that this variant produces the same pathogenic protein change or the same pathogenic splicing effect as a previously classified pathogenic or likely pathogenic variant. SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, which is below the PP3 splicing threshold of 0.2.	spliceai cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	De novo occurrence is not an applicable BRCA2 ENIGMA criterion in this framework.	cspec
PS3	Not assessed	No variant-specific damaging functional assay result was identified in the curated BRCA1/2 ENIGMA functional table or the reviewed BRCA multifactorial/functional supplement, so PS3 is not assessed.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PS4	Not assessed	No case-control study or variant-specific enrichment data were identified showing significantly increased prevalence in affected individuals, so PS4 is not assessed.	vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PM1	N/A	PM1 is not an applicable BRCA2 ENIGMA criterion in this framework.	cspec
PM2	Not met	This variant is present in population databases and therefore does not meet the ENIGMA PM2 requirement for absence from gnomAD. It is present in gnomAD v2.1 at AF 1.77165e-05 (5/282222 alleles) and in gnomAD v4.1 at AF 2.10731e-05 (34/1613428 alleles), both with 0 homozygotes.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified for occurrence in trans with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia, so PM3 is not assessed.	cspec
PM4	N/A	PM4 is not an applicable BRCA2 ENIGMA criterion in this framework.	cspec
PM5	N/A	This is not a protein-terminating variant, and no alternate pathogenic amino-acid substitution framework applies to a synonymous change, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Assumed de novo occurrence without confirmation is not an applicable BRCA2 ENIGMA criterion in this framework.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 is not assessed.	cspec
PP2	N/A	PP2 is not an applicable BRCA2 ENIGMA criterion in this framework.	cspec
PP3	Not met	Computational splicing evidence does not support a deleterious effect. SpliceAI predicts a maximum delta score of 0.06, which is below the ENIGMA PP3 splicing threshold of 0.2.	spliceai cspec vcep_specifications_v1_2_2024_11_18
PP4	Not met	Clinical-history likelihood data do not support pathogenicity. The BRCA2 clinical-history likelihood ratio for this variant is 0.284 in 12 probands, which is below the PP4 supporting threshold of 2.08.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
PP5	N/A	PP5 is not used in the BRCA2 ENIGMA framework.	cspec
BA1	Not met	Population frequency is far below the ENIGMA BA1 threshold. The highest observed filter allele frequency is 1.963e-05 in gnomAD v4.1, which is below the BA1 threshold of greater than 0.001.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Population frequency does not reach the ENIGMA BS1 threshold. The highest observed filter allele frequency is 1.963e-05 in gnomAD v4.1, which is below the BS1 supporting threshold of greater than 0.00002 and below the BS1 strong threshold of greater than 0.0001.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified for formal BS2 points assignment, so BS2 is not assessed.	cspec
BS3	Not assessed	No variant-specific benign functional assay result was identified in the curated BRCA1/2 ENIGMA functional table or the reviewed BRCA multifactorial/functional supplement, so BS3 is not assessed.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
BS4	Not assessed	No quantitative lack-of-segregation data were identified for this variant, so BS4 is not assessed.	vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
BP1	Not met	This synonymous variant does not meet BP1 because BRCA2 BP1_Strong for silent variants requires location outside a clinically important functional domain and no splicing prediction. Although SpliceAI is low at 0.06, codon 3078 lies within the BRCA2 DNA-binding domain (amino acids 2481-3186).	spliceai cspec vcep_specifications_v1_2_2024_11_18
BP2	N/A	BP2 is not an applicable BRCA2 ENIGMA criterion in this framework.	cspec
BP3	N/A	BP3 is not an applicable BRCA2 ENIGMA criterion in this framework.	cspec
BP4	Met	This synonymous variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, which is below the ENIGMA BP4 threshold of 0.1. This supports BP4 at supporting strength.	spliceai cspec vcep_specifications_v1_2_2024_11_18
BP5	Met	Clinical-history likelihood data support a benign interpretation. The BRCA2 clinical-history likelihood ratio for this variant is 0.284 in 12 probands, which is at or below the BP5 supporting threshold of 0.48 but above the BP5 moderate threshold of 0.23, supporting BP5 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 synonymous variant within the BRCA2 DNA-binding domain, and BP4 is met because SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, below the threshold of 0.1. Under the ENIGMA BRCA2 rule for silent variants inside a clinically important functional domain, this supports BP7 at supporting strength.	spliceai cspec vcep_specifications_v1_2_2024_11_18

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