Variant classification summary

NM_000059.4:c.2820A>G

BRCA2 · NP_000050.3:p.(Gln940=) · NM_000059.4

GRCh37: chr13:32911312 A>G · GRCh38: chr13:32337175 A>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

BP1_Strong BP6_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Gln940=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 NM_000059.4:c.2820A>G (p.(Gln940=), p.(Q940=)) variant has been reported in ClinVar as likely benign, including review by the ENIGMA expert panel and multiple clinical laboratories.

2

This variant is present at very low frequency in population databases, with 1/250640 alleles in gnomAD v2.1 (AF 0.00040%) and 1/1613806 alleles in gnomAD v4.1 (AF 0.00006%), which does not meet ENIGMA benign stand-alone or strong population thresholds and does not satisfy PM2 absence criteria.

3

In silico splicing analysis predicts no significant splice impact, with a SpliceAI maximum delta score of 0.00, and the synonymous p.(Gln940=) change lies outside the BRCA2 clinically important domains defined by ENIGMA, supporting BP1_Strong and arguing against PP3.

Final determination: One strong benign criterion and one supporting benign criterion meet the ENIGMA Table 3 rule for a Likely Benign 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	N/A	This synonymous variant does not create a premature stop, frameshift, or canonical +/-1,2 splice-site change, so the BRCA2 PVS1 loss-of-function framework does not apply.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not assessed	No evidence was identified that this variant has the same proven pathogenic protein or splicing consequence as a previously classified pathogenic BRCA2 variant, so PS1 was not assessed further.	cspec spliceai
PS2	N/A	De novo occurrence is not part of the ENIGMA BRCA2 framework for this review.	cspec
PS3	Not assessed	No variant-specific damaging functional study meeting the ENIGMA BRCA2 PS3 framework was identified for this variant.	vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4	Not assessed	No case-control or multifactorial evidence was identified showing this variant is significantly enriched in affected individuals compared with controls.	vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PM1	N/A	PM1 is not used in the ENIGMA BRCA2 specification for this review.	cspec
PM2	Not met	This variant is not absent from population databases, so PM2 is not met. It is present in gnomAD v2.1 at 1/250640 alleles (AF 0.00040%) and in gnomAD v4.1 at 1/1613806 alleles (AF 0.00006%).	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified for occurrence with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed further.	cspec
PM4	N/A	PM4 does not apply because this is not a protein length-changing variant, and the ENIGMA BRCA2 specification marks PM4 as not applicable.	cspec
PM5	N/A	PM5 in the ENIGMA BRCA2 framework is used for missense changes or protein-truncating variants in qualifying exons, which does not fit this synonymous variant.	cspec
PM6	N/A	Assumed de novo occurrence without confirmed parentage is not part of the ENIGMA BRCA2 framework for this review.	cspec
PP1	Not assessed	No quantitative segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not used in the ENIGMA BRCA2 specification for this review.	cspec
PP3	Not met	Available computational evidence does not support a splice-altering effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the ENIGMA PP3 threshold of 0.20.	spliceai cspec
PP4	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio supporting pathogenicity was identified for this variant, so PP4 was not assessed.	vcep_pmid_31853058_brca2_clinical_history_lr cspec
PP5	N/A	PP5 is not used in the ENIGMA BRCA2 specification for this review.	cspec
BA1	Not met	This variant does not meet the ENIGMA BA1 population threshold. It is seen only once in gnomAD v2.1 (AF 0.00040%) and once in gnomAD v4.1 (AF 0.00006%), both well below the BA1 threshold of 0.1%.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Available population data do not support BS1. The variant is observed only once in gnomAD v2.1 and once in gnomAD v4.1, and no population frequency above the ENIGMA BS1 thresholds was identified.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing occurrence in individuals without features of BRCA2-related Fanconi anemia sufficient for ENIGMA BS2 scoring.	cspec
BS3	Not assessed	No variant-specific benign functional study meeting the ENIGMA BRCA2 BS3 framework was identified for this variant.	vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Met	This is a synonymous BRCA2 variant, p.(Gln940=), located outside the clinically important BRCA2 domains defined by ENIGMA (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186), and SpliceAI predicts no splice effect with a maximum delta score of 0.00, which is below the <=0.10 threshold. This meets BP1_Strong.	cspec spliceai
BP2	N/A	BP2 is not used in the ENIGMA BRCA2 specification for this review.	cspec
BP3	N/A	BP3 is not used in the ENIGMA BRCA2 specification for this review.	cspec
BP4	N/A	ENIGMA BP4 for silent variants is limited to synonymous changes inside a clinically important domain with no predicted splice effect. This synonymous variant is outside the defined BRCA2 clinically important domains, so BP4 does not apply.	cspec spliceai
BP5	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio supporting a benign interpretation was identified for this variant, so BP5 was not assessed.	vcep_pmid_31853058_brca2_clinical_history_lr cspec
BP6	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.	cspec clinvar
BP7	Not assessed	SpliceAI predicts no splice impact, but no qualifying RNA study showing a benign transcript outcome was identified for this variant, so BP7 was not assessed beyond computational evidence alone.	spliceai vcep_humu_40_1557_s001 vcep_specifications_table9_v1_2_2024_11_18 cspec

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