Variant classification summary

NM_000059.3:c.8168A>C

BRCA2 · NP_000050.2:p.(Asp2723Ala) · NM_000059.3

GRCh37: chr13:32937507 A>C · GRCh38: chr13:32363370 A>C

Gene: BRCA2 Transcript: NM_000059.3

Final call

Likely Pathogenic

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Asp2723Ala)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.8168A>C (p.Asp2723Ala, p.D2723A) variant has been reported in ClinVar and is classified as Pathogenic by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

2

This variant is present at very low frequency in population databases, with 1/251098 alleles in gnomAD v2.1 (AF 3.98e-06) and 6/1614162 alleles in gnomAD v4.1 (AF 3.72e-06), which is too low to support a benign frequency criterion but means PM2 is not met because the variant is not absent from controls.

3

In the ENIGMA BRCA2 curated functional dataset, calibrated functional studies support PS3 Strong for this variant, indicating a damaging effect on BRCA2 function.

4

Computational evidence supports a damaging protein effect because the variant is in the BRCA2 DNA-binding region, BayesDel is 0.575545 above the PP3 threshold of 0.30, REVEL is 0.94, and SpliceAI predicts no significant splice impact (max delta score 0.00).

Final determination: One Strong pathogenic criterion together with two Supporting pathogenic criteria meets the ENIGMA Table 3 rule for a Likely Pathogenic classification.

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 fall into the BRCA2 loss-of-function categories used for PVS1, and SpliceAI predicts no significant splice effect (max delta score 0.00), so available evidence does not support a truncating or RNA loss-of-function mechanism for this change.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No qualifying reference variant with the same amino acid change and an established BRCA2 protein-based pathogenic classification was identified in the reviewed materials, so PS1 was not applied.	cspec vcep_specifications_v1_2_2024_11_18 clinvar
PS2	N/A	This VCEP framework does not use PS2 for BRCA2.	cspec
PS3	Met	In the ENIGMA BRCA2 curated functional dataset, this variant is assigned PS3 Strong because calibrated functional studies showed protein function similar to pathogenic control variants, supporting a damaging effect on BRCA2 function.	vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS4	Not met	No case-control evidence showing a statistically increased prevalence of this variant in affected individuals versus controls was identified, and the reviewed ENIGMA posterior-probability and multifactorial resources did not provide an exact variant-specific PS4-qualifying result.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	PM1 is not used as a standalone criterion in the BRCA2 specification because domain information is incorporated into the bioinformatic framework for PP3, BP4, and BP1.	cspec vcep_specifications_v1_2_2024_11_18
PM2	Not met	ENIGMA PM2_Supporting requires absence from gnomAD, but this variant is present in gnomAD v2.1 at 1/251098 alleles (AF 3.98e-06) and in gnomAD v4.1 at 6/1614162 alleles (AF 3.72e-06), so PM2 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 variant in an individual with BRCA2-related Fanconi anemia, so PM3 could not be assessed.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	PM4 is not used in this BRCA2 specification.	cspec
PM5	N/A	In this BRCA2 framework, PM5 is used for protein-termination variants in eligible exons, not for this missense substitution.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This VCEP framework does not use PM6 for BRCA2.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 could not be applied.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP2	N/A	This VCEP framework does not use PP2 for BRCA2.	cspec
PP3	Met	This missense variant lies within the BRCA2 DNA-binding functional region used by ENIGMA (amino acids 2481-3186) and has a BayesDel score of 0.575545, which is above the PP3 threshold of 0.30. REVEL is also high at 0.94, supporting a deleterious protein effect. SpliceAI predicts no significant splice impact (max delta score 0.00), so the computational evidence supports a damaging protein consequence rather than a splice mechanism.	cspec bayesdel revel spliceai vcep_specifications_v1_2_2024_11_18
PP4	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 1.329 with 2 probands, which falls in the ENIGMA neutral zone above 0.48 and below 2.08, so available clinical-history evidence does not support PP4.	PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine cspec
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is far below the BA1 threshold. In gnomAD v4.1 the highest available filter allele frequency is 1.83e-06, which is well below the ENIGMA BA1 cutoff of 0.001, so BA1 is not met.	cspec gnomad_v4 gnomad_v2
BS1	Not met	This variant does not meet the BRCA2 BS1 frequency thresholds. The highest available filter allele frequency is 1.83e-06 in gnomAD v4.1, which is below the BS1_Supporting threshold of 0.00002 and below the BS1 threshold of 0.0001.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	No qualifying adult observations or point-based evidence against BRCA2-related Fanconi anemia were identified for this variant, so BS2 could not be assessed.	cspec vcep_specifications_v1_2_2024_11_18
BS3	Not met	Available functional evidence does not support normal BRCA2 function. Instead, the curated ENIGMA functional dataset assigns PS3 Strong for this variant, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified for this variant, so BS4 could not be applied.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1	Not met	This missense variant is located within the BRCA2 DNA-binding functional region rather than outside a clinically important domain, so BP1 is not met.	cspec vcep_specifications_v1_2_2024_11_18
BP2	N/A	This VCEP framework does not use BP2 for BRCA2.	cspec
BP3	N/A	BP3 is not used in this BRCA2 specification.	cspec
BP4	Not met	Although SpliceAI predicts no significant splice impact (max delta score 0.00), the variant is in the BRCA2 DNA-binding region and the BayesDel score is 0.575545, which is above the BP4 benign threshold of 0.18. REVEL is also high at 0.94. Therefore, computational evidence does not support BP4.	cspec bayesdel revel spliceai vcep_specifications_v1_2_2024_11_18
BP5	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 1.329 with 2 probands, which is above the BP5 supporting cutoff of 0.48 and remains in the ENIGMA neutral zone, so BP5 is not met.	PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine cspec
BP6	N/A	This VCEP framework does not use BP6 for BRCA2.	cspec
BP7	Not met	This is a missense variant within the BRCA2 DNA-binding functional region, and available functional evidence supports a damaging protein effect rather than a benign RNA-only effect, so BP7 is not met.	cspec vcep_specifications_table9_v1_2_2024_11_18 spliceai

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