Variant classification summary

NM_000059.4:c.4757C>T

BRCA2 · NP_000050.3:p.(Thr1586Ile) · NM_000059.4

GRCh37: chr13:32913249 C>T · GRCh38: chr13:32339112 C>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

VUS

BP1_Strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Thr1586Ile)

gnomAD AF

6.195948097781974e-07 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.4757C>T (p.Thr1586Ile) variant has been reported in ClinVar as likely benign by one clinical laboratory.

2

This variant is absent from gnomAD v2.1 and gnomAD-Canada and is present only once in gnomAD v4.1 (1/1,613,958 alleles; AF 6.20e-07), which is far below ENIGMA benign frequency thresholds but does not meet the requirement for complete absence from controls.

3

No variant-specific functional assay result for p.(Thr1586Ile) was identified in the reviewed BRCA2 ENIGMA functional resources.

4

Computational evidence does not support a damaging effect: p.(Thr1586Ile) lies outside the BRCA2 clinically important domains used for ENIGMA missense interpretation, SpliceAI shows a maximum delta score of 0.01, BayesDel no-AF is -0.443818, and REVEL is 0.182, supporting BP1_Strong and not supporting PP3.

Final determination: BP1_Strong alone does not meet the ENIGMA Table 3 threshold for likely benign or benign classification; therefore 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 missense variant does not create a premature termination codon, frameshift, or canonical ±1,2 splice-site change, so the BRCA2 PVS1 framework is not met.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not assessed	No reviewed evidence was identified showing that another nucleotide change causing the same amino acid substitution has already been classified as pathogenic or likely pathogenic under the BRCA2 ENIGMA framework.	cspec
PS2	N/A	De novo evidence is not used for BRCA2 in this framework.	cspec
PS3	Not assessed	No variant-specific damaging functional study for p.(Thr1586Ile) was identified in the reviewed BRCA2 ENIGMA functional resources, so PS3 cannot be applied.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 oncokb
PS4	Not assessed	No case-control or multifactorial likelihood evidence showing enrichment of this variant in affected individuals was identified, so PS4 cannot be applied.	vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar
PM1	N/A	PM1 is not used for BRCA2 in this ENIGMA framework.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 and gnomAD-Canada, but it is present in gnomAD v4.1 at 1/1,613,958 alleles (AF 6.20e-07; highest population AF 8.48e-07 in European non-Finnish), so the criterion for absence from controls is not met.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No evidence was identified that this variant has been observed in trans with a pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 cannot be applied.	cspec clinvar
PM4	N/A	PM4 is not used for BRCA2 in this ENIGMA framework.	cspec
PM5	N/A	For BRCA2, PM5 is repurposed for truncating or protein-termination-codon logic rather than classic same-residue missense comparison, and this variant is missense.	pm5_candidates cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Assumed de novo evidence is not used for BRCA2 in this framework.	cspec
PP1	Not assessed	No segregation likelihood ratio or family segregation dataset was identified for this variant, so PP1 cannot be applied.	cspec clinvar
PP2	N/A	PP2 is not used for BRCA2 in this ENIGMA framework.	cspec
PP3	Not met	Computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, BayesDel no-AF is -0.443818, and p.(Thr1586Ile) lies outside the BRCA2 clinically important domains used for missense PP3 application.	cspec spliceai bayesdel revel vcep_specifications_v1_2_2024_11_18
PP4	Not assessed	No variant-specific clinical-history likelihood ratio was identified for this variant in the reviewed BRCA2 ENIGMA clinical-history resource, so PP4 cannot be applied.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
PP5	N/A	PP5 is not used in this framework.	cspec
BA1	Not met	The population frequency is far below the BA1 threshold. In gnomAD v4.1 the allele frequency is 6.20e-07, which is well below the BRCA2 BA1 threshold of 0.001.	cspec gnomad_v4
BS1	Not met	The population frequency is far below the BS1 threshold. This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 6.20e-07, which is below the BRCA2 BS1_Supporting threshold of 0.00002 and the BS1 threshold of 0.0001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No qualifying observation of this variant in individuals without Fanconi anemia features was identified under the BRCA2 point-based BS2 framework, so BS2 cannot be applied.	cspec
BS3	Not assessed	No variant-specific functional study showing normal or near-normal BRCA2 function was identified in the reviewed ENIGMA functional resources, so BS3 cannot be applied.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 oncokb
BS4	Not assessed	No quantitative non-segregation evidence was identified for this variant, so BS4 cannot be applied.	vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar
BP1	Met	This missense variant is outside the BRCA2 clinically important functional domains used by ENIGMA for missense interpretation, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, meeting BP1_Strong.	cspec spliceai vcep_specifications_v1_2_2024_11_18
BP2	N/A	BP2 is not used for BRCA2 in this ENIGMA framework.	cspec
BP3	N/A	BP3 is not used for BRCA2 in this ENIGMA framework.	cspec
BP4	N/A	BP4 is reserved in this framework for variants within clinically important domains that lack predicted impact. Because p.(Thr1586Ile) is outside those domains, benign computational evidence is captured by BP1_Strong rather than BP4.	cspec vcep_specifications_v1_2_2024_11_18
BP5	Not assessed	No variant-specific benign-direction clinical-history likelihood ratio was identified for this variant in the reviewed BRCA2 ENIGMA clinical-history resource, so BP5 cannot be applied.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
BP6	N/A	BP6 is not used in this framework.	cspec
BP7	N/A	BP7 is not applicable because this is a missense variant rather than a synonymous or qualifying intronic variant.	cspec vcep_specifications_v1_2_2024_11_18

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