NM_000059.4:c.2353A>G

BRCA2 · NP_000050.3:p.(Ile785Val) · NM_000059.4

GRCh37: chr13:32910845 A>G · GRCh38: chr13:32336708 A>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP1_Strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ile785Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 NM_000059.4:c.2353A>G (p.(Ile785Val), p.(I785V)) variant has been reported in ClinVar, with predominantly uncertain significance submissions and one likely benign submission.

This variant is present in gnomAD v2.1 at AF 1.06298e-05 (3/282226 alleles) with grpmax FAF 1.082e-05, which is below ENIGMA BA1 and BS1 thresholds and also means the variant is not absent from controls for PM2.

In a published mouse embryonic stem cell-based assay, I785V was reported as functionally indistinguishable from wild-type BRCA2; however, this variant was not identified with a preassigned PS3 or BS3 code in the ENIGMA curated functional table, so the functional evidence remains for manual review.

This missense change lies outside the BRCA2 PALB2-binding and DNA-binding domains used for ENIGMA missense pathogenicity assessment, SpliceAI predicts no splice impact (max delta 0.00), BayesDel is -0.394429, and REVEL is 0.16, supporting BP1_Strong and arguing against PP3.

Final determination: Likely Benign based on BP1_Strong under ENIGMA BRCA1/BRCA2 Table 3, which allows one strong benign criterion when multiple evidence types contribute to that code.

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 missense variant does not fall into the BRCA2 null-variant or splice-consensus categories used for PVS1, and the generic PVS1 scaffold states that it is not a nonsense, frameshift, or canonical ±1,2 splice variant.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No previously classified pathogenic or likely pathogenic reference variant producing the same amino acid change or the same predicted splice effect was identified in the retrieved evidence, so PS1 was not applied.	cspec
PS2	N/A	This criterion is designated not applicable for BRCA2 in the ENIGMA specification.	cspec
PS3	Not met	A published mouse embryonic stem cell-based assay reported I785V as functionally indistinguishable from wild-type BRCA2, which does not support a damaging functional effect. The variant was also not identified in the ENIGMA curated functional table as a PS3-coded variant.	PMID:32393398 vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4	Not met	No case-control study or ENIGMA multifactorial dataset entry was identified showing a statistically significant enrichment of this variant in affected individuals compared with controls, so PS4 was not met.	cspec
PM1	N/A	This criterion is designated not applicable for BRCA2 in the ENIGMA specification.	cspec
PM2	Not met	This variant is present in gnomAD v2.1 with 3/282226 alleles (AF 1.06298e-05; grpmax FAF 1.082e-05), so it is not absent from controls and does not meet ENIGMA PM2_Supporting.	cspec gnomad_v2
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia, so PM3 was not applied.	cspec
PM4	N/A	This criterion is designated not applicable for BRCA2 in the ENIGMA specification.	cspec
PM5	N/A	In the BRCA2 ENIGMA specification, PM5 is used for protein-truncating variants already annotated with PVS1. This missense variant does not fit that use case.	cspec
PM6	N/A	This criterion is designated not applicable for BRCA2 in the ENIGMA specification.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not applied.	cspec
PP2	N/A	This criterion is designated not applicable for BRCA2 in the ENIGMA specification.	cspec
PP3	Not met	This missense change is outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding region (aa 2481-3186) used for ENIGMA missense PP3. SpliceAI predicts no splice effect (max delta score 0.00), BayesDel is -0.394429, and REVEL is 0.16, so the available computational evidence does not support PP3.	cspec spliceai bayesdel revel
PP4	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified, so PP4 was not applied.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	This criterion is designated not applicable for BRCA2 in the ENIGMA specification.	cspec
BA1	Not met	The gnomAD v2.1 grpmax FAF is 1.082e-05, which is well below the ENIGMA BA1 threshold of 0.001, so BA1 is not met.	cspec gnomad_v2
BS1	Not met	The gnomAD v2.1 grpmax FAF is 1.082e-05, which is below the ENIGMA BS1_Supporting threshold of 0.00002 and the BS1 threshold of 0.0001, so BS1 is not met.	cspec gnomad_v2
BS2	Not assessed	No point-based evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia, so BS2 was not applied.	cspec
BS3	Not assessed	A published mouse embryonic stem cell-based assay reported I785V as functionally indistinguishable from wild-type BRCA2, which is consistent with a benign effect. However, this variant was not identified in the ENIGMA curated functional table with a preassigned BS3 code, so BS3 was left for manual review rather than applied here.	PMID:32393398 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 applied.	cspec
BP1	Met	This missense variant is outside the BRCA2 clinically important domains specified by ENIGMA for missense pathogenicity assessment (PALB2-binding aa 10-40; DNA-binding aa 2481-3186), and SpliceAI predicts no splice impact (max delta score 0.00). This supports BP1_Strong.	cspec spliceai
BP2	N/A	This criterion is designated not applicable for BRCA2 in the ENIGMA specification.	cspec
BP3	N/A	This criterion is designated not applicable for BRCA2 in the ENIGMA specification.	cspec
BP4	N/A	For BRCA2, ENIGMA BP4 applies to missense variants inside specified clinically important domains when BayesDel is ≤0.18 and SpliceAI is ≤0.1. Although this variant has no predicted splice impact (SpliceAI 0.00), a low BayesDel score (-0.394429), and a low REVEL score (0.16), it lies outside the specified domains, so BP4 is not the applicable benign computational code.	cspec spliceai bayesdel revel
BP5	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified, so BP5 was not applied.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	This criterion is designated not applicable for BRCA2 in the ENIGMA specification.	cspec
BP7	Not assessed	This is a missense variant, and no RNA study showing a normal transcript outcome was identified. Computational splice prediction alone does not justify BP7 here, so BP7 was not applied.	cspec spliceai

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