NM_000059.3:c.8362T>C

BRCA2 · NP_000050.2:p.(Trp2788Arg) · NM_000059.3

GRCh37: chr13:32944569 T>C · GRCh38: chr13:32370432 T>C

Gene: BRCA2 Transcript: NM_000059.3

Final call

Likely Pathogenic

PS3_Strong PM2_Supporting PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Trp2788Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.8362T>C (p.Trp2788Arg, p.W2788R) variant has not been observed in COSMIC and has been reported in ClinVar, including a Likely Pathogenic expert panel classification from ClinGen ENIGMA.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls and meeting PM2 at Supporting strength.

In a calibrated functional study, this variant showed protein function similar to pathogenic control variants, and the BRCA2 VCEP functional evidence table assigns PS3 at Strong strength, supporting a damaging effect on BRCA2 function.

Computational evidence supports a damaging protein effect: the variant lies in the BRCA2 DNA-binding domain, BayesDel no-AF is 0.314871, REVEL is 0.897, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.

Final determination: One Strong and three Supporting pathogenic criteria are met, which satisfies the ENIGMA BRCA1/BRCA2 Table 3 rule for Likely Pathogenic and does not meet the Table 3 threshold for Pathogenic.

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 is a missense variant, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function variant, so the BRCA2 PVS1 framework does not apply.	pvs1_gene_context pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18
PS1	Not assessed	PS1 requires a previously classified variant that produces the same amino acid change. No codon-level comparison evidence establishing that requirement was identified in the reviewed sources.	vcep_specifications_v1_2_2024_11_18
PS2	N/A	This BRCA2 VCEP framework does not use PS2 for this variant assessment context.	vcep_specifications_v1_2_2024_11_18
PS3	Met	In a calibrated functional study, this variant showed protein function similar to pathogenic control variants, supporting a damaging effect on BRCA2 protein function. The BRCA2 VCEP Table 9 assigns PS3 at Strong strength for c.8362T>C (p.Trp2788Arg).	vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447 vcep_specifications_v1_2_2024_11_18
PS4	Not met	No qualifying case-control enrichment data were identified. In the reviewed BRCA2 multifactorial dataset, this variant had a combined likelihood ratio of 1.02 and was specifically noted as not meeting the thresholds for supportive pathogenic or benign multifactorial evidence, so PS4 is not met.	vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18
PM1	N/A	Although codon 2788 lies within the BRCA2 DNA-binding region, PM1 is designated as not applicable in this BRCA2 VCEP framework.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2	Met	This variant was absent from gnomAD v2.1 and absent from gnomAD v4.1 in the reviewed population data, which is consistent with rarity in population controls and supports PM2 at Supporting strength.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
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.	vcep_specifications_v1_2_2024_11_18
PM4	N/A	PM4 is designated as not applicable in this BRCA2 VCEP framework.	vcep_specifications_v1_2_2024_11_18
PM5	N/A	The BRCA2 VCEP PM5 framework reviewed here is for protein-truncating variants in eligible exons. This variant is missense, so that PM5 framework does not apply.	vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PM6	N/A	This BRCA2 VCEP framework does not use PM6 for this variant assessment context.	vcep_specifications_v1_2_2024_11_18
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.	vcep_specifications_v1_2_2024_11_18
PP2	N/A	PP2 is designated as not applicable in this BRCA2 VCEP framework.	vcep_specifications_v1_2_2024_11_18
PP3	Met	This missense variant is located in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.314871, which is above the BRCA2 PP3 threshold of 0.30 for a damaging protein effect. REVEL is also high at 0.897. SpliceAI predicts no significant splice effect with a maximum delta score of 0.03, so the computational evidence supports a protein-level damaging interpretation rather than a splicing effect.	bayesdel revel spliceai vcep_specifications_v1_2_2024_11_18
PP4	Not met	In the BRCA2 clinical-history likelihood-ratio table, this variant had a likelihood ratio of 1.22 based on 1 proband. That value is below the PP4 Supporting threshold of 2.08, so PP4 is not met.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	vcep_specifications_v1_2_2024_11_18 clinvar
BA1	Not met	This variant was absent from the reviewed gnomAD datasets and therefore is well below the BRCA2 BA1 threshold of filter allele frequency greater than 0.001. BA1 is not met.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS1	Not met	This variant was absent from the reviewed gnomAD datasets and therefore does not reach the BRCA2 BS1 thresholds of filter allele frequency greater than 0.00002 or greater than 0.0001. BS1 is not met.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS2	Not assessed	No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified for points-based BS2 assessment, so BS2 was not assessed.	vcep_specifications_v1_2_2024_11_18
BS3	Not met	Available calibrated functional evidence supports a damaging effect rather than normal function. The BRCA2 VCEP Table 9 assigns PS3 Strong for this variant, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447 vcep_specifications_v1_2_2024_11_18
BS4	Not assessed	No quantitative non-segregation analysis with a likelihood ratio at or below the BRCA2 BS4 thresholds was identified, so BS4 was not assessed.	vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Not met	BP1_Strong for BRCA2 is limited to silent, missense, or in-frame variants outside clinically important domains with no predicted splice impact. This variant is within the BRCA2 DNA-binding domain, so BP1 is not met.	spliceai vcep_specifications_v1_2_2024_11_18
BP2	N/A	BP2 is designated as not applicable in this BRCA2 VCEP framework.	vcep_specifications_v1_2_2024_11_18
BP3	N/A	BP3 is designated as not applicable in this BRCA2 VCEP framework.	vcep_specifications_v1_2_2024_11_18
BP4	Not met	For a missense variant in a clinically important BRCA2 domain, BP4 requires BayesDel no-AF 0.18 or lower and SpliceAI 0.1 or lower. SpliceAI is low at 0.03, but BayesDel is 0.314871, which is above the benign threshold, so BP4 is not met.	bayesdel spliceai vcep_specifications_v1_2_2024_11_18
BP5	Not met	In the BRCA2 clinical-history likelihood-ratio table, this variant had a likelihood ratio of 1.22 based on 1 proband. That value is above the BP5 benign thresholds and falls in the neutral zone above 0.48 and below 2.08, so BP5 is not met.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
BP6	N/A	BP6 is designated as not applicable in this BRCA2 VCEP framework.	vcep_specifications_v1_2_2024_11_18
BP7	N/A	BP7 in this BRCA2 framework is used for silent or intronic variants, or for specific RNA-only evidence contexts. This is a missense variant in a clinically important domain, so BP7 is not applicable.	vcep_specifications_v1_2_2024_11_18 spliceai

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