Variant classification summary

NM_000059.4:c.831T>G

BRCA2 · NP_000050.3:p.(Asn277Lys) · NM_000059.4

GRCh37: chr13:32906446 T>G · GRCh38: chr13:32332309 T>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Benign

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Asn277Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.831T>G (p.Asn277Lys) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1/2 expert panel.

2

This variant is present in population databases, including gnomAD v2.1 at AF 0.0000687 with a highest observed filter allele frequency of 0.0001033 and gnomAD v4.1 at AF 0.0001886 with a highest observed filter allele frequency of 0.0002296, supporting BS1.

3

Calibrated functional data in the ENIGMA BRCA1/2 specification support no damaging effect on protein function for p.(Asn277Lys), supporting BS3.

4

In silico evidence does not suggest splice disruption, with a SpliceAI maximum delta score of 0.00, and the missense change lies outside the BRCA2 clinically important domains used by ENIGMA for missense interpretation, supporting BP1_Strong.

Final determination: Benign based on multiple strong benign criteria under the ENIGMA BRCA1/2 Table 3 combining rules; this variant meets BS1_Strong, BS3_Strong, and BP1_Strong, with additional supporting benign evidence from BP6.

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 variant is a missense substitution, p.(Asn277Lys), and does not fall into the BRCA2 loss-of-function variant categories used for PVS1 such as nonsense, frameshift, initiation codon, or canonical +/-1,2 splice site variants.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified showing that this variant produces the same protein change or the same proven splicing effect as a previously established pathogenic BRCA2 variant.	cspec clinvar spliceai
PS2	N/A	No confirmed de novo occurrence data were identified, and this criterion is not applicable based on the available BRCA2 ENIGMA framework for this case.	cspec
PS3	Not met	Available calibrated functional evidence does not support a damaging effect. ENIGMA Table 9 lists this variant as showing protein function similar to benign control variants, so PS3 is not met.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No standalone case-control evidence was identified showing that this variant is significantly enriched in affected individuals compared with controls at the ENIGMA PS4 threshold.	cspec clinvar
PM1	N/A	PM1 is not applicable in the BRCA2 ENIGMA framework for this case, and this variant is not located in a BRCA2 region used here for PM1-based assertion.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.0000687 (19/276526 alleles) and in gnomAD v4.1 at AF 0.0001886 (303/1606240 alleles), so the ENIGMA PM2 absence-from-controls requirement is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified of this variant occurring with another BRCA2 variant in a patient with phenotype consistent with BRCA2-related Fanconi anemia, so PM3 cannot be assessed.	cspec
PM4	N/A	This variant is a missense substitution and not a protein length-changing in-frame event, so PM4 is not applicable.	cspec
PM5	N/A	In the BRCA2 ENIGMA framework reviewed for this case, PM5 is used for protein-terminating variant contexts and does not apply to this missense substitution.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	No assumed or confirmed de novo data were identified, and this criterion is not applicable based on the available BRCA2 ENIGMA framework for this case.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified showing that this variant tracks with disease in affected relatives, so PP1 cannot be applied.	cspec
PP2	N/A	PP2 is not applicable in the BRCA2 ENIGMA framework for this case.	cspec
PP3	Not met	Available predictive evidence does not support a damaging effect under the BRCA2 ENIGMA PP3 rule. This missense variant is outside the ENIGMA clinically important domains, and SpliceAI shows no predicted splice impact with a max delta score of 0.00, which is below the PP3 splice threshold of 0.20.	cspec spliceai
PP4	Not assessed	No qualifying multifactorial clinical-history likelihood ratio was identified for this variant, so PP4 cannot be applied.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not applied in this framework because external assertions alone are not used as independent pathogenic evidence.	cspec clinvar
BA1	Not met	The population frequency does not meet the ENIGMA BA1 threshold. The highest observed filter allele frequency is 0.0001033 in gnomAD v2.1 and 0.0002296 in gnomAD v4.1, both below the BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Met	This variant is present in gnomAD at a frequency above the ENIGMA BS1 strong threshold. In gnomAD v2.1, the highest observed filter allele frequency is 0.0001033 in the European (non-Finnish) population, which is above the BS1 strong threshold of 0.0001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that permits ENIGMA BS2 point assignment.	cspec
BS3	Met	Calibrated functional evidence supports no damaging effect. ENIGMA Table 9 lists c.831T>G (p.(Asn277Lys)) as BS3 Strong because one calibrated study found protein function similar to benign control variants.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative non-segregation analysis was identified showing lack of segregation with disease at an ENIGMA BS4 likelihood ratio threshold.	cspec
BP1	Met	This missense variant affects codon 277, which is outside the BRCA2 clinically important domains used by ENIGMA for missense interpretation (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186), and SpliceAI predicts no splice effect with a max delta score of 0.00, which is at or below the BP1 threshold of 0.10. This supports BP1_Strong.	cspec spliceai
BP2	N/A	No phased co-occurrence data were identified, and BP2 is not applicable in the BRCA2 ENIGMA framework for this case.	cspec
BP3	N/A	BP3 is not applicable in the BRCA2 ENIGMA framework for this case.	cspec
BP4	N/A	Under the BRCA2 ENIGMA framework, BP4 for missense variants applies within clinically important functional domains with no predicted impact. This variant is outside those domains, so benign missense evidence is captured by BP1_Strong rather than BP4.	cspec spliceai
BP5	Not assessed	No qualifying multifactorial clinical-history likelihood ratio in the benign direction was identified for this variant, so BP5 cannot be applied.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	N/A	This is a missense variant, not a silent or qualifying intronic variant, and no RNA assay evidence was identified to support BP7-based benign splicing interpretation.	cspec spliceai

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