NM_000059.4:c.4516T>C

BRCA2 · NP_000050.3:p.(Phe1506Leu) · NM_000059.4

GRCh37: chr13:32913008 T>C · GRCh38: chr13:32338871 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.(Phe1506Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.4516T>C (p.Phe1506Leu; p.F1506L) variant has been reported in ClinVar with conflicting classifications, including uncertain significance and likely benign submissions.

This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (3/1,613,958 alleles; AF 0.00019%), with the highest observed frequency 1/6,062 alleles in the Middle Eastern population (AF 0.01650%).

No variant-specific calibrated functional assay classification was identified in the reviewed BRCA2 ENIGMA functional tables, and no variant-specific reviewed functional evidence was identified in curated somatic reviewer resources.

The substitution lies outside the BRCA2 clinically important domains defined by ENIGMA, SpliceAI predicts no significant splice effect (max delta score 0.00), and missense predictor scores are low (REVEL 0.093; BayesDel no-AF -0.650576), supporting a benign computational profile.

Final determination: A single strong benign criterion, without an additional benign criterion from a distinct evidence type, does not meet ENIGMA BRCA1/BRCA2 Table 3 thresholds for Likely Benign or Benign classification; 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 variant is a missense substitution, not a nonsense, frameshift, canonical ±1/2 splice, or other predicted loss-of-function variant, and SpliceAI predicts no significant splice effect (max delta score 0.00). Available evidence does not support applying PVS1 or PVS1(RNA).	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No qualifying previously classified pathogenic or likely pathogenic variant causing the same amino acid change or the same predicted splice effect was identified from the available evidence, so PS1 was not applied.	cspec clinvar
PS2	N/A	PS2 is not used in this BRCA2 VCEP framework.	cspec
PS3	Not assessed	No variant-specific calibrated functional study assignment supporting a damaging effect was identified for this variant, so PS3 was not applied.	vcep_specifications_table9_v1_2_2024_11_18 oncokb cspec
PS4	Not assessed	No case-control study, odds ratio, or other qualifying evidence showing increased prevalence in affected individuals was identified for this variant, so PS4 was not applied.	cspec clinvar vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	PM1 is not used as a standalone criterion in this BRCA2 VCEP framework because domain context is incorporated into other criteria.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 3/1,613,958 alleles (AF 0.00019%), with the highest observed frequency 1/6,062 alleles in the Middle Eastern population (AF 0.01650%). ENIGMA BRCA2 applies PM2 only for variants absent from control datasets, so PM2 was not applied.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 pathogenic variant in an individual with a BRCA2-related Fanconi anemia phenotype, so PM3 was not applied.	cspec
PM4	N/A	PM4 is not used in this BRCA2 VCEP framework.	cspec
PM5	N/A	In this BRCA2 VCEP framework, PM5 is restricted to protein-truncating variants under the PM5_PTC rules. This variant is a missense substitution, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not used in this BRCA2 VCEP framework.	cspec
PP1	Not assessed	No quantitative co-segregation evidence was identified for this variant, so PP1 was not applied.	cspec clinvar
PP2	N/A	PP2 is not used in this BRCA2 VCEP framework.	cspec
PP3	Not met	This missense variant lies outside the BRCA2 clinically important domains used by the ENIGMA BRCA2 framework, and SpliceAI predicts no significant splice effect (max delta score 0.00). Missense predictor scores are low, with REVEL 0.093 and BayesDel no-AF -0.650576, which are not consistent with the ENIGMA PP3 thresholds for pathogenic computational evidence, so PP3 was not applied.	cspec spliceai revel bayesdel
PP4	Not assessed	No exact-variant multifactorial clinical likelihood ratio meeting the ENIGMA PP4 threshold was identified, so PP4 was not applied.	cspec PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_17924331_easton_2007_ajhg
PP5	N/A	PP5 is not for use in this VCEP framework.	cspec
BA1	Not assessed	This variant is present in gnomAD v4.1, but the ENIGMA BRCA2 BA1 rule is based on filter allele frequency from specified gnomAD datasets, and no qualifying BA1-level filter allele frequency was retrieved. BA1 was not applied.	cspec gnomad_v4
BS1	Not assessed	This variant is present in gnomAD v4.1, including 1/6,062 alleles in the Middle Eastern population (AF 0.01650%), but the ENIGMA BRCA2 BS1 rule is based on filter allele frequency from specified gnomAD datasets, and no qualifying BS1 filter allele frequency was retrieved. BS1 was not applied.	cspec gnomad_v4
BS2	Not assessed	No point-based evidence from unaffected or non-Fanconi anemia observations was identified for this variant, so BS2 was not applied.	cspec
BS3	Not assessed	No variant-specific calibrated functional study assignment showing no damaging effect was identified for this variant, so BS3 was not applied.	vcep_specifications_table9_v1_2_2024_11_18 oncokb cspec
BS4	Not assessed	No quantitative non-segregation evidence or segregation likelihood ratio against pathogenicity was identified for this variant, so BS4 was not applied.	cspec clinvar vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Met	This missense variant lies outside the BRCA2 clinically important domains defined by the ENIGMA BRCA2 framework (PALB2-binding domain amino acids 10-40 and DNA-binding domain amino acids 2481-3186), and SpliceAI predicts no significant splice effect (max delta score 0.00). This meets BRCA2 BP1_Strong.	cspec spliceai
BP2	N/A	BP2 is not used in this BRCA2 VCEP framework.	cspec
BP3	N/A	BP3 is not used in this BRCA2 VCEP framework.	cspec
BP4	Not met	SpliceAI predicts no significant splice effect (max delta score 0.00), REVEL is low at 0.093, and BayesDel no-AF is -0.650576, consistent with a benign computational profile. However, ENIGMA BRCA2 applies BP4 for missense variants only when they are inside a clinically important domain, and p.(Phe1506Leu) lies outside those domains, so BP4 was not applied.	cspec spliceai revel bayesdel
BP5	Not assessed	No exact-variant multifactorial clinical likelihood ratio meeting the ENIGMA BP5 threshold was identified, so BP5 was not applied.	cspec PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_17924331_easton_2007_ajhg
BP6	N/A	BP6 is not used in this BRCA2 VCEP framework.	cspec
BP7	Not assessed	No variant-specific RNA study showing a normal transcript outcome was identified for this missense variant, so BP7 was not applied.	cspec spliceai

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.