NM_000059.3:c.794-2A>G

BRCA2 · NP_000050.2:p.? · NM_000059.3

GRCh37: chr13:32906407 A>G · GRCh38: chr13:32332270 A>G

Gene: BRCA2 Transcript: NM_000059.3

Final call

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.794-2A>G (p.?) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel classifies it as uncertain significance, while other submitters have reported likely pathogenic or pathogenic interpretations.

This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 at an overall allele frequency of 6.260650932398744e-07 (1/1597278 alleles; 0 homozygotes), indicating that it is very rare in population databases.

In the ENIGMA BRCA2 exon-level splice/PVS1 table, this exact splice acceptor variant is associated with observed in-frame exon 10 skipping and assigned PVS1_N/A (RNA), so current VCEP evidence does not support treating it as a qualifying loss-of-function event under PVS1.

SpliceAI predicts strong splice impact for this variant with a maximum delta score of 0.99 (DS_AL 0.99, DS_AG 0.31), but the BRCA2 ENIGMA framework does not apply PP3 to canonical ±1,2 splice-site variants and this splice prediction should not be double-counted against the variant-specific RNA/PVS1 assessment.

Final determination: No pathogenic or benign ACMG/AMP criteria were met; therefore the variant does not satisfy ENIGMA Table 3 thresholds for pathogenic, likely pathogenic, likely benign, or benign classification and 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	N/A	This canonical splice acceptor variant is specifically addressed in the ENIGMA BRCA2 exon-level PVS1 table, where c.794-2A>G is linked to observed in-frame exon 10 skipping and assigned PVS1_N/A (RNA). Although BRCA2 loss of function is an established disease mechanism, the current VCEP variant-specific RNA evidence does not support applying PVS1 to this variant.	vcep_specifications_table4_v1_2_2024_11_18 cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	Available evidence does not identify a previously classified pathogenic or likely pathogenic BRCA2 variant with the same demonstrated splice consequence as this variant. The ENIGMA exon table distinguishes c.794-2A>G from nearby donor-site variants with different transcript outcomes, so PS1 is not supported.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PS2	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this review context, and no confirmed de novo data were identified.	cspec
PS3	Not met	No calibrated functional assay evidence supporting a damaging effect was identified for this variant under the ENIGMA PS3 framework. The available variant-specific RNA evidence is handled through the PVS1 RNA framework rather than PS3, and it does not support PVS1 application here.	vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4	Not assessed	No case-control study or quantified enrichment analysis showing that this variant is significantly more common in affected individuals than in controls was identified. Current evidence is insufficient to assess PS4.	clinvar vcep_humu_40_1557_s001 cspec
PM1	N/A	PM1 is not applicable in the BRCA2 ENIGMA framework because domain information is incorporated into the bioinformatic rules rather than used as a separate criterion, and this variant is a canonical splice-site change rather than a missense or in-frame variant in a critical protein domain.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 but is present once in gnomAD v4.1 at an overall allele frequency of 6.260650932398744e-07 (1/1597278 alleles; 0 homozygotes). Under the BRCA2 ENIGMA specification, observation of a variant only once in an outbred population is not informative, and a VCEP-qualified PM2_Supporting determination was not established from the available population data.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia. PM3 cannot be assessed from the current evidence.	cspec
PM4	N/A	PM4 is not applicable in the BRCA2 ENIGMA framework, and this variant is not an in-frame insertion or deletion.	cspec
PM5	N/A	The BRCA2 ENIGMA PM5_PTC rule is used for protein-terminating variants that are already annotated as PVS1. Because this variant has a variant-specific ENIGMA assignment of PVS1_N/A (RNA), PM5 is not applicable.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PM6	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this review context, and no assumed de novo evidence was identified.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so a quantitative co-segregation likelihood ratio supporting pathogenicity could not be established.	cspec
PP2	N/A	PP2 is not applicable in the BRCA2 ENIGMA specification.	cspec
PP3	N/A	SpliceAI predicts a strong splice effect for this variant with a maximum delta score of 0.99 (DS_AL 0.99, DS_AG 0.31). However, the BRCA2 ENIGMA bioinformatic rule does not apply PP3 to canonical ±1,2 splice-site variants, and the generic PVS1 scaffold also cautions against double-counting splice prediction evidence in this setting.	spliceai cspec pvs1_variant_assessment
PP4	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified. The reviewed BRCA2 clinical-history likelihood-ratio workbook did not yield an exact match for c.794-2A>G.	vcep_pmid_31853058_brca2_clinical_history_lr cspec
PP5	N/A	PP5 is not used in the BRCA2 ENIGMA specification.	cspec
BA1	Not met	The observed population frequency is far below the ENIGMA BA1 threshold. This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 at an overall allele frequency of 6.260650932398744e-07, which is below the BA1 threshold of 0.001.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The observed population frequency is far below the ENIGMA BS1 thresholds. This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 at an overall allele frequency of 6.260650932398744e-07, which is below the supporting threshold of 0.00002 and the strong threshold of 0.0001.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that would satisfy the ENIGMA BS2 point-based framework.	cspec
BS3	Not met	No well-established functional study showing no damaging effect was identified for this variant. The reviewed curated ENIGMA functional table did not provide a benign functional assignment for c.794-2A>G.	vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so a quantitative likelihood ratio supporting BS4 could not be established.	cspec
BP1	N/A	BP1 is intended for silent, missense, or in-frame variants outside clinically important domains without splice impact. This variant is a canonical splice acceptor change, so BP1 does not apply.	cspec spliceai
BP2	N/A	BP2 is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
BP3	N/A	BP3 is not applicable in the BRCA2 ENIGMA specification, and this variant is not an in-frame change in a repetitive region.	cspec
BP4	N/A	BP4 is not supported because this variant is at a canonical splice acceptor position and SpliceAI predicts strong splice impact with a maximum delta score of 0.99. The BRCA2 ENIGMA BP4 rule is intended for variants without predicted splice impact and does not fit this variant.	spliceai bayesdel cspec
BP5	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified. The reviewed BRCA2 clinical-history likelihood-ratio workbook did not yield an exact match for c.794-2A>G.	vcep_pmid_31853058_brca2_clinical_history_lr cspec
BP6	N/A	BP6 is not applicable in the BRCA2 ENIGMA specification.	cspec
BP7	N/A	BP7 does not apply because this variant is a canonical -2 splice acceptor change rather than a synonymous variant or a deep intronic variant outside the conserved splice motif. In addition, SpliceAI predicts strong splice impact with a maximum delta score of 0.99.	spliceai cspec

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