Variant classification summary

NM_000059.4:c.3941A>G

BRCA2 · NP_000050.3:p.(Lys1314Arg) · NM_000059.4

GRCh37: chr13:32912433 A>G · GRCh38: chr13:32338296 A>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

VUS

BP1 strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Lys1314Arg)

gnomAD AF

2.5333034403527373e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP1 (Strong): the missense change p.(Lys1314Arg) lies outside the BRCA2 PALB2-binding and DNA-binding domains, with no predicted splice impact (SpliceAI maximum delta 0.001).

2

Overall: classified as a variant of uncertain significance, because a single Strong benign criterion (BP1) does not meet the ENIGMA Likely Benign combination rule and no pathogenic criteria are met.

Final determination: Under ENIGMA BRCA2 v1.2 Table 3, one Strong benign criterion alone is Likely Benign only when multiple evidence types are present; BP1_Strong alone therefore results in VUS.

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	Not met: this is a missense substitution, p.(Lys1314Arg), not a null variant, with SpliceAI maximum delta 0.001.	cspec spliceai PMID:16683254
PS1	Not assessed	Not assessed: no previously classified pathogenic or likely pathogenic same-amino-acid substitution at Lys1314 was identified as a comparator.	cspec spliceai PMID:16683254
PS2	N/A	Does not apply: the ENIGMA BRCA2 v1.2 specification marks PS2 not applicable, and no de novo parentage evidence was available.	cspec
PS3	Not assessed	Not assessed: no validated functional assay for p.(Lys1314Arg) was available, so no damaging protein-function result could be used.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:16683254
PS4	Not assessed	Not assessed: no case-control analysis meeting p<=0.05 and OR>=4 was available, only a single family report.	cspec vcep_supplementarytables_v1_2_2024_11_18 PMID:16683254
PM1	N/A	Does not apply: the specification marks PM1 not applicable, and residue Lys1314 lies outside the PALB2-binding (aa 10-40) and DNA-binding (aa 2481-3186) domains.	cspec vcep_appendices_v1_2_2024_11_18
PM2	Not met	Not met: the variant is present in controls (gnomAD v2.1 AF 4.51e-06; v4.1 AF 2.53e-06), so it is not absent from population databases.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no second pathogenic BRCA2 variant, phase information, or Fanconi anemia phenotype data were available to establish trans co-occurrence.	cspec PMID:16683254
PM4	N/A	Does not apply: the specification marks PM4 not applicable, and this missense substitution does not change protein length.	cspec
PM5	N/A	Does not apply: PM5 in BRCA2 v1.2 covers protein-termination variants, and this exon 11 missense change has no qualifying comparator.	cspec vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates
PM6	N/A	Does not apply: the ENIGMA BRCA2 v1.2 specification marks PM6 not applicable, and no assumed de novo evidence was documented.	cspec
PP1	Not assessed	Not assessed: no cosegregation likelihood ratio or affected-relative genotypes were available, and a single family report does not establish segregation.	cspec PMID:16683254
PP2	N/A	Does not apply: the governing ENIGMA BRCA2 v1.2 specification explicitly marks PP2 not applicable.	cspec
PP3	Not met	Not met: the variant lies outside the BRCA2 functional domains and its BayesDel no-AF score is -0.521, below the 0.30 threshold.	cspec bayesdel
PP4	Not assessed	Not assessed: the clinical-history likelihood-ratio table has no c.3941A>G row, so no combined multifactorial clinical LR was available.	cspec vcep_pmid_31853058_brca2_clinical_history_lr
PP5	Not met	Not met: the exact ClinVar record has zero expert-panel submissions, so no expert-panel pathogenic assertion exists for this variant.	clinvar
BA1	Not met	Not met: gnomAD v2.1 AF 4.51e-06 and v4.1 AF 2.53e-06 are far below the 0.1% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest reported subpopulation AF, 9.74e-06 in gnomAD v2.1, is below the 0.002% BS1 supporting threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no proband-level phenotype, chromosome-breakage, or Fanconi anemia clinical-feature data were available for this variant.	cspec
BS3	Not assessed	Not assessed: no validated benign functional assay for p.(Lys1314Arg) was available, so no benign protein-function result could be used.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:16683254
BS4	Not assessed	Not assessed: no cosegregation likelihood ratio or documented non-segregation in affected family members was available.	cspec PMID:16683254
BP1	Met	Met at Strong: the missense change Lys1314Arg lies outside the BRCA2 PALB2-binding and DNA-binding domains, with no predicted splice impact (SpliceAI max delta 0.001).	cspec spliceai
BP2	N/A	Does not apply: the ClinGen ENIGMA BRCA2 VCEP specification explicitly designates BP2 not applicable.	cspec
BP3	N/A	Does not apply: the specification designates BP3 not applicable, and this is a missense substitution, not an in-frame indel.	cspec
BP4	Not met	Not met: BP4 for missense variants is limited to the BRCA2 functional domains, and Lys1314 lies outside the PALB2-binding (aa 10-40) and DNA-binding (aa 2481-3186) domains.	cspec bayesdel
BP5	Not assessed	Not assessed: the clinical-history likelihood-ratio table has no c.3941A>G row, so no combined benign-direction LR was supplied.	cspec vcep_pmid_31853058_brca2_clinical_history_lr
BP6	Not met	Not met: the exact ClinVar record has zero expert-panel submissions, so no expert-panel benign assertion exists for this variant.	clinvar
BP7	Not met	Not met: BP7 covers silent or qualifying intronic variants, whereas this is a missense change with no mRNA assay available.	cspec

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