Variant classification summary

NM_000059.4:c.7879A>T

BRCA2 · NP_000050.3:p.(Ile2627Phe) · NM_000059.4

GRCh37: chr13:32936733 A>T · GRCh38: chr13:32362596 A>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

PS3_Strong PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ile2627Phe)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.7879A>T (p.Ile2627Phe) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar as Pathogenic, including review by the ClinGen ENIGMA BRCA1/2 expert panel.

2

This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 at 4/1614168 alleles (AF 2.47806e-06; 0 homozygotes; grpmax FAF 7.9e-07), which is well below benign population thresholds but does not satisfy ENIGMA absence-based PM2.

3

Calibrated functional evidence supports a damaging effect on BRCA2 protein function, and ENIGMA Table 9 assigns PS3 Strong for c.7879A>T (p.Ile2627Phe).

4

The variant lies within the BRCA2 DNA-binding domain, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.07.

Final determination: ENIGMA BRCA1/BRCA2 Table 3 does not support a Likely Pathogenic or Pathogenic classification with 1 strong pathogenic criterion and 1 supporting pathogenic criterion, so the classification remains 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 splice-site, initiation-codon, or exon-level loss-of-function variant, so PVS1 is not met for this BRCA2 change.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not assessed	No same-amino-acid pathogenic comparison variant was identified in the retrieved evidence, so PS1 was not independently assessed.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	No de novo data were identified, and this criterion is not applied in the BRCA2 ENIGMA framework used here.	cspec
PS3	Met	This variant has calibrated functional evidence showing a damaging effect on BRCA2 protein function. ENIGMA Table 9 assigns PS3 Strong for c.7879A>T (p.Ile2627Phe), with three calibrated studies reported as supportive of abnormal protein function.	vcep_specifications_table9_v1_2_2024_11_18 oncokb
PS4	Not assessed	This variant has been reported in ClinVar and once in COSMIC, and ENIGMA supplementary material lists a posterior pathogenicity of 0.9977 with IARC class 5. However, the retrieved materials do not cleanly separate prevalence-in-affected evidence from other multifactorial components for independent PS4 assignment, so PS4 was not applied in this pass.	clinvar vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PM1	N/A	PM1 is not applied as a separate criterion in the BRCA2 ENIGMA framework because domain-based missense interpretation is incorporated into the PP3/BP4 bioinformatic rules.	cspec vcep_specifications_v1_2_2024_11_18
PM2	Not met	This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 at 4/1,614,168 alleles (AF 2.47806e-06; 0 homozygotes), so it is not absent from control datasets and PM2 is not met.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified for biallelic BRCA2 disease, Fanconi anemia phenotype, or a qualifying in-trans co-occurring BRCA2 pathogenic variant, so PM3 was not assessed.	cspec
PM4	N/A	This criterion is not applicable in the BRCA2 ENIGMA framework used here.	cspec
PM5	Not assessed	No qualifying alternate pathogenic missense variant at the same codon was identified in the retrieved evidence, and the exon-level PM5_PTC framework is for protein-truncating variants rather than this missense substitution, so PM5 was not assessed.	cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PM6	N/A	This criterion is not applicable in the BRCA2 ENIGMA framework used here.	cspec
PP1	Not assessed	No quantitative co-segregation likelihood ratio was identified, so PP1 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PP2	N/A	This criterion is not applicable in the BRCA2 ENIGMA framework used here.	cspec
PP3	Not assessed	This missense variant lies within the BRCA2 DNA-binding domain, but SpliceAI predicts no significant splice effect (max delta score 0.07, below the PP3 splice threshold of 0.2). The official BRCA2 missense PP3 rule also requires BayesDel no-AF at or above 0.30, and that score was not identified in the retrieved evidence, so PP3 was not independently applied.	cspec spliceai vcep_specifications_v1_2_2024_11_18
PP4	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 0.68 from 3 probands, which is below the PP4 Supporting threshold of 2.08, so PP4 is not met.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	The gnomAD v4.1 grpmax filter allele frequency is 7.9e-07, which is below the BA1 threshold of 0.001 (0.1%), so BA1 is not met.	gnomad_v4 cspec
BS1	Not met	The gnomAD v4.1 grpmax filter allele frequency is 7.9e-07, which is below the BS1 Supporting threshold of 0.00002 and well below the BS1 Strong threshold of 0.0001, so BS1 is not met.	gnomad_v4 cspec
BS2	Not assessed	No qualifying observations of this variant in individuals without Fanconi anemia features were identified for BRCA2 BS2 scoring, so BS2 was not assessed.	cspec
BS3	Not met	Available calibrated functional evidence does not show normal BRCA2 protein function. Instead, ENIGMA Table 9 assigns PS3 Strong for damaging functional results, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation likelihood ratio was identified, so BS4 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
BP1	Not met	This missense variant is within the BRCA2 DNA-binding domain (amino acids 2481-3186), so it does not meet the BP1 requirement for a missense or silent variant outside a clinically important domain. SpliceAI is low at 0.07, but the domain requirement is not satisfied.	cspec spliceai vcep_specifications_v1_2_2024_11_18
BP2	N/A	This criterion is not applicable in the BRCA2 ENIGMA framework used here.	cspec
BP3	N/A	This criterion is not applicable in the BRCA2 ENIGMA framework used here.	cspec
BP4	Not assessed	SpliceAI predicts no significant splice impact (max delta score 0.07, within the BP4 splice threshold of 0.1), and the variant is within the BRCA2 DNA-binding domain. However, the official BRCA2 missense BP4 rule also requires BayesDel no-AF at or below 0.18, and that score was not identified in the retrieved evidence, so BP4 was not independently applied.	cspec spliceai vcep_specifications_v1_2_2024_11_18
BP5	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 0.68 from 3 probands, which is above the BP5 Supporting threshold of 0.48, so BP5 is not met.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
BP6	N/A	This criterion is not applicable in the BRCA2 ENIGMA framework used here.	cspec
BP7	Not met	Although mRNA evidence in ENIGMA Table 9 notes no aberration and SpliceAI is low at 0.07, this is a missense variant within the BRCA2 DNA-binding domain, and BRCA2 BP7 for missense variants in a clinically important domain requires BS3 to be met. Because functional evidence supports PS3 Strong rather than BS3, BP7 is not met.	vcep_specifications_table9_v1_2_2024_11_18 spliceai cspec vcep_specifications_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.