Variant classification summary

NM_000059.4:c.9976A>T

BRCA2 · NP_000050.3:p.(Lys3326Ter) · NM_000059.4

GRCh37: chr13:32972626 A>T · GRCh38: chr13:32398489 A>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

Benign

BA1 BS1 BS3 BP6

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Lys3326Ter)

gnomAD AF

ClinVar

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.9976A>T (p.Lys3326Ter, K3326*) variant has been observed in somatic cancers in COSMIC (18 occurrences) and has been reported in ClinVar with an expert-panel benign classification.

2

This variant is common in population databases, including gnomAD v2.1 with an overall allele frequency of 0.64680% and grpmax FAF of 0.849119%, and gnomAD v4.1 with an overall allele frequency of 0.79156%; these values are above the BRCA2 ENIGMA BA1 (>0.1%) and BS1 (>0.01%) thresholds.

3

Calibrated BRCA2 functional evidence supports a benign effect, with the expert specification assigning BS3 Strong to this exact variant based on protein function similar to benign controls.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07.

Final determination: Benign based on BA1 as a stand-alone benign criterion under the ENIGMA BRCA1/BRCA2 Table 3 combining rules; BS1_Strong and BS3_Strong are also independently consistent with a benign 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	N/A	This nonsense variant occurs in BRCA2 exon 27, but the BRCA2 expert specification marks protein-termination variants in exon 27 after p.Glu3309 as PVS1_N/A. p.Lys3326Ter lies beyond this cutoff, so loss-of-function evidence is not counted under PVS1 for this variant.	cspec vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	PS1 is defined in this specification for predicted missense substitutions or variants with the same predicted splice effect as a previously classified pathogenic variant. This variant is a nonsense change, so PS1 is not applicable.	cspec
PS2	Not assessed	No confirmed de novo data with parental relationships and phenotypic specificity were identified, so PS2 was not assessed.	cspec
PS3	Not met	Available functional evidence does not support a damaging effect. The BRCA2 expert specification lists this exact variant as BS3 Strong, reporting protein function similar to benign control variants, so PS3 is not met.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not met	Available evidence does not show the marked enrichment in affected individuals required for PS4. The retrieved BRCA2 expert materials did not identify qualifying case-control evidence for pathogenic enrichment of this variant, and the reference-set materials list it as likely benign rather than supporting increased prevalence in affected individuals.	cspec vcep_supplementarytables_v1_2_2024_11_18 clinvar
PM1	N/A	PM1 is not applicable in the BRCA2 expert specification for this variant type. This variant is a distal nonsense change and is not being evaluated as a missense variant within a clinically important functional domain.	cspec
PM2	Not met	This variant is not absent from population databases. In gnomAD v2.1, the overall allele frequency is 0.00646801 (0.64680%) with grpmax FAF 0.00849119, which is far above the PM2 requirement for absence from controls.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for this variant in trans with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not applicable in this BRCA2 expert framework for this variant.	cspec
PM5	N/A	The BRCA2 expert specification excludes PM5_PTC for exon 27 protein-termination variants after p.Glu3309. Because p.Lys3326Ter is beyond this cutoff, PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is marked not applicable in this BRCA2 expert specification.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.	cspec vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg
PP2	N/A	PP2 is marked not applicable in this BRCA2 expert specification.	cspec
PP3	N/A	PP3 in the BRCA2 expert specification is used for missense, in-frame, or non-canonical splice-relevant variants. This variant is a nonsense change, and SpliceAI does not predict significant splice disruption (max delta score 0.07), so PP3 is not applicable.	cspec spliceai
PP4	Not assessed	No qualifying multifactorial clinical likelihood ratio supporting pathogenicity was identified for this variant, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_17924331_easton_2007_ajhg
PP5	N/A	PP5 is marked not applicable in this BRCA2 expert specification.	cspec
BA1	Met	This variant is common in population databases. In gnomAD v2.1, grpmax FAF is 0.00849119 (0.849119%), which is above the BRCA2 ENIGMA BA1 threshold of 0.001 (0.1%); the overall allele frequency is 0.00646801 (0.64680%), and gnomAD v4.1 also shows an overall allele frequency of 0.00791559 (0.79156%).	cspec gnomad_v2 gnomad_v4
BS1	Met	The population frequency is also above the BRCA2 ENIGMA BS1 threshold. In gnomAD v2.1, grpmax FAF is 0.00849119 (0.849119%), which is above the BS1 Strong threshold of 0.0001 (0.01%).	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No point-based evidence in unaffected individuals without features of BRCA2-related Fanconi anemia was identified, so BS2 was not assessed.	cspec
BS3	Met	Calibrated functional evidence in the BRCA2 expert specification supports a benign effect. This exact variant is listed as BS3 Strong, with protein function similar to benign control variants; SpliceAI also predicts no significant splice impact (max delta score 0.07).	cspec vcep_specifications_table9_v1_2_2024_11_18 spliceai
BS4	Not assessed	No quantitative lack-of-segregation likelihood ratio was identified for this variant, so BS4 was not assessed.	cspec vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg
BP1	N/A	BP1 in the BRCA2 expert specification is used for silent, missense, or in-frame variants outside clinically important functional domains with no splice effect. This variant is a nonsense change, so BP1 is not applicable.	cspec spliceai
BP2	N/A	BP2 is marked not applicable in this BRCA2 expert specification.	cspec
BP3	N/A	BP3 is marked not applicable in this BRCA2 expert specification.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact for this variant (max delta score 0.07), but BP4 in the BRCA2 expert specification is defined for missense, in-frame, silent, or eligible intronic variants. This nonsense variant is not eligible for BP4.	cspec spliceai
BP5	Not assessed	No qualifying multifactorial clinical likelihood ratio against pathogenicity was identified in the retrieved structured BRCA2 materials, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_17924331_easton_2007_ajhg
BP6	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	N/A	BP7 in the BRCA2 expert specification is defined for silent or intronic variants, and in some RNA-only scenarios for missense or in-frame variants outside key domains. This nonsense variant is not eligible for BP7.	cspec spliceai

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