Variant classification summary

NM_000059.4:c.9227G>T

BRCA2 · NP_000050.3:p.(Gly3076Val) · NM_000059.4

GRCh37: chr13:32954253 G>T · GRCh38: chr13:32380116 G>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Pathogenic

PS3_Strong PM2_Supporting PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Gly3076Val)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.9227G>T (p.Gly3076Val) variant has not been observed in COSMIC and has been reported in ClinVar, where the overall classification is Pathogenic with expert panel review by the ClinGen ENIGMA BRCA1/BRCA2 Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.

3

A calibrated BRCA2 functional assay summarized in ENIGMA Table 9 supports a damaging effect on protein function, and this evidence meets PS3 at Strong strength.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07, which is below the ENIGMA PP3 splice threshold of 0.20 and below the BP4 splice threshold of 0.10.

Final determination: One Strong and two Supporting pathogenic criteria meet the ENIGMA Table 3 rule for a Likely Pathogenic 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	Not met	This variant is a missense change, NM_000059.4:c.9227G>T (p.Gly3076Val, p.G3076V), and does not fall into the BRCA2 null-variant categories used for PVS1. No RNA-only evidence was identified to show a transcript effect that would justify PVS1(RNA).	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not assessed	No previously established pathogenic BRCA2 variant producing the same amino acid substitution was identified in the reviewed sources, so PS1 was not adjudicated from the available evidence.	cspec clinvar
PS2	N/A	De novo evidence is not an applicable ENIGMA BRCA2 criterion in this framework.	cspec
PS3	Met	This variant has a calibrated BRCA2 functional assay result showing a damaging effect on protein function. ENIGMA Table 9 assigns PS3 Strong for c.9227G>T (p.Gly3076Val).	vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4	Not assessed	No case-control comparison or quantified enrichment in affected individuals versus controls was identified from the available evidence, so PS4 was not adjudicated.	cspec clinvar
PM1	N/A	PM1 is not used in the ENIGMA BRCA2 framework.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which supports rarity in population databases and is consistent with PM2_Supporting.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified for this variant in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not adjudicated.	cspec
PM4	N/A	PM4 is not used in the ENIGMA BRCA2 framework.	cspec
PM5	N/A	In the ENIGMA BRCA2 framework, PM5 is defined here for protein-truncating variants in eligible exons. This variant is missense, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Assumed de novo occurrence without confirmed parentage is not an applicable ENIGMA BRCA2 criterion in this framework.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not adjudicated.	cspec
PP2	N/A	PP2 is not used in the ENIGMA BRCA2 framework.	cspec
PP3	Not assessed	SpliceAI predicts no significant splice impact for this variant (max delta score 0.07), which is below the ENIGMA PP3 splice threshold of 0.20. Although residue 3076 lies within the BRCA2 DNA-binding region, no BayesDel no-AF score was identified in the available evidence to complete the ENIGMA missense PP3 rule.	spliceai cspec
PP4	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 0.776 in 1 proband, which is below the PP4 supporting threshold of 2.08. This value does not support pathogenic clinical-history evidence.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
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 gnomAD v4.1 and therefore is far below the BA1 stand-alone benign threshold of FAF greater than 0.001.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below both the BS1 supporting threshold of FAF greater than 0.00002 and the BS1 strong threshold of FAF greater than 0.0001.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified to score BS2.	cspec
BS3	Not met	Available calibrated functional evidence shows a damaging effect on BRCA2 protein function rather than normal function, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4	Not assessed	No quantitative evidence showing lack of segregation with disease was identified for this variant, so BS4 was not adjudicated.	cspec
BP1	Not met	This missense variant affects residue 3076 within the BRCA2 DNA-binding region (amino acids 2481-3186), so it is not outside a clinically important functional domain. Available functional evidence also supports a damaging effect, which argues against BP1_Strong.	cspec vcep_specifications_table9_v1_2_2024_11_18
BP2	N/A	BP2 is not used in the ENIGMA BRCA2 framework.	cspec
BP3	N/A	BP3 is not used in the ENIGMA BRCA2 framework.	cspec
BP4	Not met	SpliceAI predicts no significant splice impact for this variant (max delta score 0.07, below the BP4 splice threshold of 0.10), but ENIGMA BP4 for a missense variant inside a clinically important domain also requires BayesDel no-AF less than or equal to 0.18 and no predicted impact via protein change. Those benign missense conditions were not met from the available evidence, and calibrated functional data support a damaging effect.	spliceai cspec vcep_specifications_table9_v1_2_2024_11_18
BP5	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 0.776 in 1 proband, which is above the BP5 supporting threshold of 0.48. This value falls in the neutral zone and does not support benign clinical-history evidence.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
BP6	N/A	BP6 is not used in the ENIGMA BRCA2 framework.	cspec
BP7	N/A	BP7 in this framework is for silent or specified intronic variants, whereas NM_000059.4:c.9227G>T is a missense variant.	cspec spliceai

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