NM_000059.4:c.2259T>C

BRCA2 · NP_000050.3:p.(Phe753=) · NM_000059.4

GRCh37: chr13:32910751 T>C · GRCh38: chr13:32336614 T>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

BP1_Strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Phe753=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.2259T>C (p.Phe753=) variant has been reported in ClinVar with only likely benign submissions.

This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 3/1614118 alleles (AF 1.8586e-06; grpmax FAF 6.8e-07), which is far below ENIGMA BRCA2 BA1 and BS1 thresholds but does not satisfy absence from controls for PM2.

SpliceAI predicts no meaningful splice effect for this synonymous change (max delta score 0.00), and codon 753 lies outside the ENIGMA-defined BRCA2 clinically important domains, supporting BP1_Strong and not supporting PP3 or PVS1.

Final determination: BP1_Strong is present as a single strong benign criterion, but this alone does not satisfy the ENIGMA Table 3 thresholds for likely benign or benign classification; the variant is therefore classified as of 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 within the BRCA2 null-variant or canonical splice-site categories used for PVS1, and SpliceAI predicts no splice disruption (max delta score 0.00), so available evidence does not support a loss-of-function effect for this criterion.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No evidence was identified that this variant produces the same proven pathogenic protein or splice consequence as a previously classified pathogenic or likely pathogenic BRCA2 variant, so PS1 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	The ENIGMA BRCA2 specification marks de novo evidence as not applicable for this gene framework, so PS2 was not applied.	cspec
PS3	Not assessed	No calibrated BRCA2 functional assay result for this exact variant was identified in the reviewed BRCA2 functional datasets, so PS3 was not assessed.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not assessed	No case-control study or quantitative enrichment data showing a significant excess of this variant in affected individuals was identified, so PS4 was not assessed.	cspec clinvar vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	The ENIGMA BRCA2 specification marks PM1 as not applicable, so this criterion was not applied.	cspec
PM2	Not met	This variant is not absent from controls because it is present in gnomAD v4.1 at 3/1,614,118 alleles (AF 1.8586e-06; grpmax FAF 6.8e-07), so available population data do not support PM2.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	The ENIGMA BRCA2 specification marks PM4 as not applicable, so this criterion was not applied.	cspec
PM5	N/A	In the ENIGMA BRCA2 framework, PM5 is repurposed for truncating or protein-termination-codon logic rather than classic same-residue missense comparison, and this synonymous variant does not meet that use case.	cspec pm5_candidates
PM6	N/A	The ENIGMA BRCA2 specification marks assumed de novo evidence as not applicable, so PM6 was not applied.	cspec
PP1	Not assessed	No quantitative co-segregation data for this variant were identified, so PP1 was not assessed.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP2	N/A	The ENIGMA BRCA2 specification marks PP2 as not applicable, so this criterion was not applied.	cspec
PP3	Not met	SpliceAI predicts no meaningful splice effect for this synonymous variant (max delta score 0.00), which is below the ENIGMA BRCA2 PP3 splice threshold of 0.2, so PP3 is not met.	cspec spliceai
PP4	Not assessed	No exact match for this variant was identified in the BRCA2 clinical-history likelihood-ratio table, so there is no quantitative multifactorial clinical-history evidence to support PP4 at this time.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	The ENIGMA BRCA2 specification marks PP5 as not applicable, so this criterion was not applied.	cspec
BA1	Not met	The observed gnomAD v4.1 grpmax FAF is 6.8e-07, which is well below the ENIGMA BRCA2 BA1 threshold of greater than 0.001, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	The observed gnomAD v4.1 grpmax FAF is 6.8e-07, which is below both the ENIGMA BRCA2 BS1 Supporting threshold of greater than 0.00002 and the Strong threshold of greater than 0.0001, so BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified that this variant was observed under the ENIGMA BRCA2 unaffected or non-Fanconi-anemia conditions required for BS2 point assignment, so BS2 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
BS3	Not assessed	No calibrated BRCA2 functional or RNA assay demonstrating no damaging effect for this exact variant was identified, so BS3 was not assessed.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4	Not assessed	No quantitative non-segregation data for this variant were identified, so BS4 was not assessed.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1	Met	This is a synonymous BRCA2 variant outside the ENIGMA-defined clinically important domains, and SpliceAI predicts no splice effect (max delta score 0.00, below the <=0.1 threshold), which meets BP1_Strong.	cspec vcep_specifications_v1_2_2024_11_18 spliceai
BP2	N/A	The ENIGMA BRCA2 specification marks BP2 as not applicable, so this criterion was not applied.	cspec
BP3	N/A	The ENIGMA BRCA2 specification marks BP3 as not applicable, so this criterion was not applied.	cspec
BP4	Not met	SpliceAI predicts no splice effect (max delta score 0.00), but the ENIGMA BRCA2 BP4 rule for silent variants is limited to synonymous variants inside clinically important domains; this variant is at codon 753, outside those domains, so BP4 is not met.	cspec vcep_specifications_v1_2_2024_11_18 spliceai
BP5	Not assessed	No exact match for this variant was identified in the BRCA2 clinical-history likelihood-ratio table, so there is no quantitative multifactorial clinical-history evidence to support BP5 at this time.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	The ENIGMA BRCA2 specification marks BP6 as not applicable, so this criterion was not applied.	cspec
BP7	Not assessed	SpliceAI predicts no splice effect (max delta score 0.00), but no variant-specific RNA study showing normal transcript processing was identified, and this outside-domain synonymous variant does not meet the ENIGMA BP7 supporting rule that is limited to silent variants inside clinically important domains with BP4 met. BP7 was therefore not assessed.	cspec vcep_specifications_v1_2_2024_11_18 spliceai vcep_specifications_table9_v1_2_2024_11_18

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.