Variant classification summary

NM_000059.3:c.8242G>A

BRCA2 · NP_000050.2:p.(Gly2748Ser) · NM_000059.3

GRCh37: chr13:32937581 G>A · GRCh38: chr13:32363444 G>A

Gene: BRCA2 Transcript: NM_000059.3

Final call

VUS

PS3_Strong PP3_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Gly2748Ser)

gnomAD AF

3.71732471574857e-06 (v4.1)

ClinVar

Uncertain Significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.8242G>A (p.Gly2748Ser; G2748S) variant has been reported in ClinVar, where the current expert-panel overall classification is uncertain significance, while multiple clinical laboratory submissions classify it as likely pathogenic or pathogenic.

2

This variant is present at very low frequency in population databases, including gnomAD v2.1 at 3/249070 alleles (AF 1.20e-05; grpmax FAF 9.58e-06) and gnomAD v4.1 at 6/1614064 alleles (AF 3.72e-06), which is below ENIGMA BS1 and BA1 thresholds but means PM2 is not met because the variant is not absent from controls.

3

In the ENIGMA BRCA2 functional evidence table, this exact variant is assigned PS3 at strong strength based on one calibrated study reported to show a damaging functional effect consistent with pathogenic control variants.

4

This missense change lies within the BRCA2 DNA-binding domain; BayesDel no-AF is 0.454479, above the ENIGMA PP3 threshold of 0.30, SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, and REVEL is 0.842, supporting a damaging protein effect without predicted splice disruption.

Final determination: PS3_Strong plus PP3_Supporting does not meet the ENIGMA Table 3 threshold for Likely Pathogenic or Pathogenic, and no benign rule combination is met; the variant is therefore 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 is not a nonsense, frameshift, canonical ±1/2 splice-site, initiation-codon, or deletion event, and no RNA-only evidence was identified to support a null-effect mechanism. Available evidence does not support applying PVS1 for this variant.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No validated same-amino-acid pathogenic or likely pathogenic comparator was identified in the reviewed materials, so PS1 was not assessed from the currently available evidence.	cspec
PS2	N/A	PS2 is not used in this BRCA2 ENIGMA framework.	cspec
PS3	Met	In the ENIGMA BRCA2 functional evidence table, this exact variant, c.8242G>A (p.Gly2748Ser), is assigned PS3 at strong strength based on one calibrated functional study reported to show a damaging effect consistent with pathogenic control variants.	vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control study or quantitative enrichment analysis for this exact variant was identified in the reviewed materials. Available evidence is insufficient to determine whether the prevalence in affected individuals is significantly increased over controls.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar
PM1	N/A	PM1 is not applied as an independent criterion in the BRCA2 ENIGMA framework because domain information is incorporated into the bioinformatic code logic instead.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at 3/249070 alleles (AF 1.20e-05) and in gnomAD v4.1 at 6/1614064 alleles (AF 3.72e-06), so the ENIGMA requirement for absence from controls is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 pathogenic or likely pathogenic variant in an individual with BRCA2-related Fanconi anemia. PM3 was therefore not assessed.	cspec
PM4	N/A	PM4 is not used in this BRCA2 ENIGMA framework.	cspec
PM5	N/A	For BRCA2 in this ENIGMA framework, PM5 is repurposed for protein-truncating variant logic rather than classic same-residue missense comparisons. Because this is a missense variant, PM5 is not applicable.	cspec pm5_candidates
PM6	N/A	PM6 is not used in this BRCA2 ENIGMA framework.	cspec
PP1	Not assessed	No quantitative co-segregation analysis or family-based likelihood ratio meeting ENIGMA thresholds was identified for this variant. PP1 was not assessed from the available evidence.	cspec vcep_pmid_17924331_easton_2007_ajhg clinvar
PP2	N/A	PP2 is not used in this BRCA2 ENIGMA framework.	cspec
PP3	Met	This missense variant lies within the BRCA2 DNA-binding domain, a clinically important functional region used by the ENIGMA bioinformatic framework. BayesDel no-AF is 0.454479, which is above the ENIGMA PP3 threshold of 0.30, SpliceAI shows no significant splice effect with a maximum delta score of 0.06, and REVEL is 0.842; together these findings support a damaging protein effect and meet PP3 at supporting strength.	cspec bayesdel spliceai revel
PP4	Not assessed	No exact-variant clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified. The reviewed BRCA2 clinical-history likelihood-ratio table did not provide a usable entry for this variant, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not used in this BRCA2 ENIGMA framework.	cspec
BA1	Not met	The population data are well below the ENIGMA BA1 threshold. The gnomAD v2.1 group maximum filter allele frequency is 9.58e-06, which is below the BA1 cutoff of 0.001.	cspec gnomad_v2
BS1	Not met	The population frequency does not reach the ENIGMA BS1 thresholds. The gnomAD v2.1 group maximum filter allele frequency is 9.58e-06, which is below both the BS1 supporting threshold of 2.0e-05 and the BS1 strong threshold of 1.0e-04.	cspec gnomad_v2
BS2	Not assessed	No qualifying observations in adults without BRCA2-related Fanconi anemia features were identified to score BS2 under the ENIGMA point-based framework. BS2 was not assessed from the available evidence.	cspec
BS3	Not met	Available functional evidence does not support a benign effect. Instead, the ENIGMA BRCA2 functional evidence table assigns this exact variant PS3 at strong strength based on a calibrated damaging functional result, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation likelihood ratio meeting ENIGMA BS4 thresholds was identified for this variant. BS4 was not assessed from the available evidence.	cspec vcep_pmid_17924331_easton_2007_ajhg vcep_supplementarytables_v1_2_2024_11_18
BP1	Not met	This missense variant does not meet BP1 because it lies within the BRCA2 DNA-binding domain, which is a clinically important functional region in the ENIGMA framework. BP1 is reserved for missense, silent, or in-frame variants outside these regions with no predicted splice impact.	cspec spliceai
BP2	N/A	BP2 is not used in this BRCA2 ENIGMA framework.	cspec
BP3	N/A	BP3 is not used in this BRCA2 ENIGMA framework.	cspec
BP4	Not met	BP4 is not met. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, the variant is inside the BRCA2 DNA-binding domain and the BayesDel no-AF score is 0.454479, which is above the BP4 benign threshold of 0.18 and instead supports predicted protein impact.	cspec bayesdel spliceai revel
BP5	Not assessed	No exact-variant clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified. The reviewed BRCA2 clinical-history likelihood-ratio table did not provide a usable entry for this variant, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not used in this BRCA2 ENIGMA framework.	cspec
BP7	N/A	BP7 does not apply because this is a missense variant. In the BRCA2 ENIGMA framework, BP7 is reserved for specific synonymous, intronic, or RNA-only contexts.	cspec

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.