NM_000059.3:c.8009C>G

BRCA2 · NP_000050.2:p.(Ser2670Trp) · NM_000059.3

GRCh37: chr13:32937348 C>G · GRCh38: chr13:32363211 C>G

Gene: BRCA2 Transcript: NM_000059.3

Final call

VUS

PM2_Supporting PP5_Supporting BP4_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Ser2670Trp)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.8009C>G (p.Ser2670Trp) variant has not been observed in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls and meeting PM2_Supporting under the BRCA2 VCEP framework.

In the BRCA2 VCEP functional assay table, this variant is recorded with splice alteration evidence including exon 18 deletion, but the reviewed evidence was not accepted for PS3 or BS3 code application, so neither functional criterion is met from the available curated data.

For computational evidence, REVEL is 0.825, but the BRCA2 VCEP rule uses BayesDel and SpliceAI; BayesDel no-AF is 0.159332 and SpliceAI max delta score is 0.03, which supports BP4 and does not meet PP3 thresholds.

Final determination: Using the ENIGMA BRCA1/BRCA2 v1.2 conflicting-evidence point system, PM2_Supporting (+1) and PP5_Supporting (+1) offset by BP4_Supporting (-1) yield a net score of 1 point, which falls within the Uncertain Significance range.

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 is a missense substitution, NM_000059.3:c.8009C>G (p.Ser2670Trp), rather than a nonsense, frameshift, canonical ±1/2 splice-site, initiation-codon, or exon-level deletion/duplication variant. SpliceAI predicts no significant splice effect (max delta score 0.03), so available evidence does not support applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No previously established pathogenic or likely pathogenic variant causing the same amino acid change or the same predicted splicing outcome was identified in the reviewed materials, so PS1 was not assessed from the available evidence.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	De novo occurrence evidence is not used in this BRCA2 specification, so PS2 is not applicable.	cspec
PS3	Not met	In the BRCA2 VCEP functional table, this variant is recorded as a missense variant with splice alteration evidence, including exon 18 deletion, but the available evidence was not accepted for PS3 code application. The table states that results from one calibrated study with a cDNA-based design were not considered for code application, so PS3 is not met.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control study or other reviewed dataset was identified showing that this variant is significantly enriched in affected individuals with an odds ratio of at least 4 and p value of 0.05 or less. Available evidence is insufficient to assess PS4.	cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	PM1 is not applied in this BRCA2 specification because domain and hotspot information are incorporated into the bioinformatic framework rather than used as a separate criterion.	cspec vcep_specifications_v1_2_2024_11_18
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which supports rarity in population controls under the BRCA2 VCEP framework. This meets PM2 at supporting strength.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic BRCA2 variant in a proband with phenotype consistent with BRCA2-related Fanconi anemia. PM3 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	PM4 is not used in this BRCA2 specification.	cspec
PM5	N/A	For BRCA2, PM5 is repurposed for protein-truncating-variant logic rather than classic same-residue missense comparison. Because this is a missense variant and the PM5 candidate review marked classic same-residue PM5 as ineligible, PM5 is not applicable.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Assumed de novo evidence is not used in this BRCA2 specification, so PM6 is not applicable.	cspec
PP1	Not assessed	No quantitative co-segregation analysis or family likelihood ratio for this variant was identified in the reviewed materials, so PP1 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PP2	N/A	PP2 is not used in this BRCA2 specification.	cspec
PP3	Not met	This missense variant lies within the BRCA2 DNA-binding region used by the BRCA2 VCEP bioinformatic framework, but the computational thresholds for PP3 are not met. BayesDel no-AF is 0.159332, which is below the pathogenic threshold of 0.30, and SpliceAI max delta score is 0.03, which is below the splice threshold of 0.2. REVEL is 0.825, but the BRCA2 VCEP rule uses BayesDel and SpliceAI rather than REVEL for PP3/BP4 adjudication.	cspec vcep_appendices_v1_2_2024_11_18 bayesdel spliceai revel
PP4	Not assessed	The BRCA2 clinical-history likelihood-ratio workbook did not identify an entry for this exact variant, so no variant-specific multifactorial clinical-history likelihood ratio was available to assess PP4.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
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 absent from gnomAD v2.1 and absent from gnomAD v4.1, so its population frequency is well below the BA1 stand-alone benign threshold of filter allele frequency greater than 0.1%. BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so its population frequency is below the BS1 thresholds of filter allele frequency above 0.002% or 0.01%. BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified for this variant, so BS2 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
BS3	Not met	In the BRCA2 VCEP functional table, this variant is recorded as having splice alteration evidence, including exon 18 deletion, but the available evidence was not accepted for BS3 code application. The table states that PS3 and BS3 are not met for this variant.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative non-segregation analysis or family likelihood ratio against pathogenicity was identified for this variant, so BS4 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BP1	Not met	This missense variant is located within the BRCA2 DNA-binding region (amino acids 2481-3186), which is treated as a clinically important functional domain in the BRCA2 VCEP framework. Because BP1_Strong requires a missense or silent variant outside a clinically important functional domain and with no predicted splice effect, BP1 is not met.	cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2	N/A	BP2 is not used in this BRCA2 specification except in the context of BS2, and no such BS2 context was identified here.	cspec
BP3	N/A	BP3 is not used in this BRCA2 specification.	cspec
BP4	Met	This missense variant lies within the BRCA2 DNA-binding region used by the BRCA2 VCEP bioinformatic framework, and computational evidence supports no predicted impact under that rule. BayesDel no-AF is 0.159332, which is at or below the BP4 threshold of 0.18, and SpliceAI max delta score is 0.03, which is at or below the BP4 threshold of 0.1. These findings support BP4 at supporting strength.	cspec vcep_appendices_v1_2_2024_11_18 bayesdel spliceai
BP5	Not assessed	The BRCA2 clinical-history likelihood-ratio workbook did not identify an entry for this exact variant, so no variant-specific multifactorial clinical-history likelihood ratio was available to assess BP5.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not used in this BRCA2 specification.	cspec
BP7	N/A	BP7 in this BRCA2 specification is intended for silent or intronic variants, or for RNA-only evidence showing no damaging splice effect in qualifying settings. This is a missense variant, and the reviewed functional table did not support a benign RNA-based code for this variant, so BP7 is not applicable.	cspec vcep_specifications_table9_v1_2_2024_11_18 spliceai

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