NM_000059.3:c.9227G>T

BRCA2 · NP_000050.2:p.(Gly3076Val) · NM_000059.3

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

Gene: BRCA2 Transcript: NM_000059.3

Final call

Likely Pathogenic

PS3_Strong PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Gly3076Val)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.9227G>T (p.Gly3076Val) variant has not been observed in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification from ClinGen ENIGMA.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity, although the site-level depth information required for formal ENIGMA PM2_Supporting application was not identified here.

In the ENIGMA BRCA2 calibrated functional dataset, p.(Gly3076Val) showed abnormal function similar to pathogenic control variants, supporting PS3 at strong strength.

This missense change lies within the BRCA2 DNA-binding domain; BayesDel no-AF is 0.377938, REVEL is 0.884, and SpliceAI max delta is 0.07, supporting a damaging protein effect without a predicted splice effect and therefore supporting PP3 but not BP4.

Final determination: Under ENIGMA BRCA1/2 Table 3, one Strong pathogenic criterion together with two Supporting pathogenic criteria supports 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 substitution, not a nonsense, frameshift, initiation-loss, or canonical ±1,2 splice variant. SpliceAI predicts no significant splice effect (max delta 0.07), so available evidence does not support a BRCA2 loss-of-function mechanism for PVS1.	pvs1_gene_context pvs1_variant_assessment cspec spliceai vcep_specifications_v1_2_2024_11_18
PS1	Not assessed	No previously classified variant with the same proven amino-acid change or the same demonstrated splice effect was identified here, so PS1 could not be assessed from the available evidence.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	De novo occurrence is not an applicable criterion in this BRCA2 ENIGMA framework for this review.	cspec
PS3	Met	In the ENIGMA BRCA2 calibrated functional dataset, c.9227G>T (p.Gly3076Val) showed abnormal function similar to pathogenic control variants, supporting PS3 at strong strength.	vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control study, odds ratio, or other quantitative prevalence evidence meeting the ENIGMA PS4 rule was identified here.	clinvar vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18
PM1	N/A	PM1 is not an applicable criterion in this BRCA2 ENIGMA framework for this review.	cspec
PM2	Not assessed	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity. However, the ENIGMA PM2_Supporting rule also requires adequate local read depth, and site-level depth information was not identified here.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 could not be assessed.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	PM4 is not an applicable criterion in this BRCA2 ENIGMA framework for this review.	cspec
PM5	N/A	In this BRCA2 ENIGMA framework, PM5 is defined for protein-truncating variants already annotated with PVS1. This variant is a missense substitution, so that PM5 rule does not apply.	cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PM6	N/A	PM6 is not an applicable criterion in this BRCA2 ENIGMA framework for this review.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be assessed.	cspec vcep_specifications_v1_2_2024_11_18
PP2	N/A	PP2 is not an applicable criterion in this BRCA2 ENIGMA framework for this review.	cspec
PP3	Met	This missense variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186). BayesDel no-AF is 0.377938, which is above the ENIGMA PP3 threshold of 0.30, REVEL is 0.884, and SpliceAI predicts no significant splice effect (max delta 0.07), supporting a damaging protein effect consistent with PP3.	cspec bayesdel revel spliceai vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PP4	Not met	The BRCA2 clinical-history likelihood ratio for c.9227G>T is 0.776 with 1 proband, which is below the ENIGMA PP4 supporting threshold of 2.08. This value does not support PP4.	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 Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BA1 threshold of filter allele frequency greater than 0.1%.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BS1 thresholds of filter allele frequency greater than 0.002% or 0.01%.	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 the ENIGMA BS2 point-based rule, so BS2 could not be assessed.	cspec vcep_specifications_v1_2_2024_11_18
BS3	Not met	Available calibrated functional evidence showed an abnormal damaging effect rather than normal function, so BS3 is not supported for this variant.	vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BS4	Not assessed	No non-segregation data with a quantitative likelihood ratio were identified for this variant, so BS4 could not be assessed.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18
BP1	Not met	This missense variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), so it does not meet the ENIGMA BP1 rule, which is limited to missense or silent changes outside clinically important functional domains with no predicted splice effect.	cspec spliceai vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BP2	N/A	BP2 is not an applicable criterion in this BRCA2 ENIGMA framework for this review.	cspec
BP3	N/A	BP3 is not an applicable criterion in this BRCA2 ENIGMA framework for this review.	cspec
BP4	Not met	Although SpliceAI predicts no significant splice effect (max delta 0.07, below the BP4 threshold of 0.1), BayesDel no-AF is 0.377938, which is above the benign BP4 threshold of 0.18. Available computational evidence therefore does not support BP4.	cspec bayesdel spliceai vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BP5	Not met	The BRCA2 clinical-history likelihood ratio for c.9227G>T is 0.776 with 1 proband, which is above the ENIGMA BP5 supporting threshold of 0.48. This value does not support BP5.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
BP6	N/A	BP6 is not an applicable criterion in this BRCA2 ENIGMA framework for this review.	cspec
BP7	Not met	This is a missense variant within a clinically important BRCA2 functional domain, and no RNA evidence showing a benign transcript effect was identified. Available evidence therefore does not support BP7.	cspec spliceai vcep_specifications_v1_2_2024_11_18

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