Variant classification summary

NM_000059.3:c.2471T>C

BRCA2 · NP_000050.2:p.(Leu824Ser) · NM_000059.3

GRCh37: chr13:32910963 T>C · GRCh38: chr13:32336826 T>C

Gene: BRCA2 Transcript: NM_000059.3

Final call

Likely Benign

BP1_Strong BP6_Supporting_Benign

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Leu824Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.2471T>C (p.Leu824Ser) variant has not been observed in COSMIC and has been reported in ClinVar, where the current expert-panel classification is likely benign.

2

This variant is present at low frequency in population databases, including 2/237562 alleles in gnomAD v2.1 and 4/1602664 alleles in gnomAD v4.1, with v2.1 grpmax FAF 1.975e-05 and v4.1 grpmax FAF 2.98e-05; these values are below the ENIGMA BA1 and BS1 thresholds and do not support PM2 because the variant is not absent from controls.

3

Computational evidence supports a benign interpretation under the BRCA2 ENIGMA framework because p.Leu824Ser lies outside the BRCA2 clinically important domains used for missense evaluation, SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, BayesDel is -0.270943, and REVEL is 0.261, supporting BP1_Strong and not supporting PP3.

4

The BRCA2 clinical-history likelihood ratio is 0.60 in 2 probands, which falls in the neutral zone and does not support either PP4 or BP5.

Final determination: One strong benign criterion and one supporting benign criterion are present, which meets the ENIGMA Table 3 rule for a Likely 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	Not met	This missense variant does not fall into the BRCA2 PVS1 null-variant categories, and no RNA evidence showing a loss-of-function transcript effect was identified. Available evidence therefore does not support applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No same-amino-acid pathogenic or likely pathogenic comparator variant was verified for this amino acid change, so PS1 was not assessed from the available evidence.	cspec clinvar
PS2	N/A	The ENIGMA BRCA2 specification does not use PS2 for this gene framework, so this criterion is not applicable.	cspec
PS3	Not met	No calibrated functional study result for BRCA2 p.(Leu824Ser) was identified in the reviewed BRCA2 functional resources, so available evidence does not support PS3.	cspec vcep_specifications_table9_v1_2_2024_11_18 oncokb
PS4	Not met	Available evidence does not show a statistically significant enrichment of this variant in affected individuals compared with controls, so PS4 is not met.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar
PM1	N/A	PM1 is not used in the ENIGMA BRCA2 specification for this framework, so this criterion is not applicable.	cspec
PM2	Not met	This variant is present in population databases, so it is not absent from controls. In gnomAD v2.1 it is seen at 2/237562 alleles with grpmax FAF 1.975e-05, and in gnomAD v4.1 it is seen at 4/1602664 alleles with grpmax FAF 2.98e-05; these findings do not support PM2.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not used in the ENIGMA BRCA2 specification for this framework, so this criterion is not applicable.	cspec
PM5	Not met	This is a missense variant rather than a protein-truncating variant, and the BRCA2 ENIGMA PM5 rule in the reviewed materials is the PM5_PTC framework for qualifying truncating variants. Available evidence therefore does not support PM5.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	The ENIGMA BRCA2 specification does not use PM6 for this gene framework, so this criterion is not applicable.	cspec
PP1	Not met	No quantitative co-segregation data were identified for this variant, so available evidence does not support PP1.	cspec clinvar
PP2	N/A	The ENIGMA BRCA2 specification does not use PP2 for this gene framework, so this criterion is not applicable.	cspec
PP3	Not met	Computational evidence does not meet the BRCA2 ENIGMA PP3 thresholds. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, below the PP3 splice threshold of 0.2, and this residue lies outside the BRCA2 clinically important domains used for missense PP3. BayesDel is -0.270943 and REVEL is 0.261, which do not provide VCEP support for PP3 here.	cspec spliceai bayesdel revel
PP4	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 0.60 in 2 probands, which is below the ENIGMA PP4 supporting threshold of 2.08. This does not support PP4.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	The ENIGMA BRCA2 specification does not use PP5 for this framework, so this criterion is not applicable.	cspec
BA1	Not met	Population frequency does not reach the BRCA2 ENIGMA BA1 threshold. The highest observed grpmax FAF is 1.975e-05 in gnomAD v2.1 and 2.98e-05 in gnomAD v4.1, both well below the BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not meet the BRCA2 ENIGMA BS1 threshold in the reviewed evidence. In gnomAD v2.1 the grpmax FAF is 1.975e-05, which is below the BS1 supporting threshold of >2.0e-05 and far below the BS1 strong threshold of >1.0e-04.	cspec gnomad_v2
BS2	Not assessed	No point-based evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 framework, so BS2 was not assessed.	cspec
BS3	Not met	No calibrated benign functional result for BRCA2 p.(Leu824Ser) was identified in the reviewed BRCA2 functional resources, so available evidence does not support BS3.	cspec vcep_specifications_table9_v1_2_2024_11_18 oncokb
BS4	Not met	No quantitative lack-of-segregation evidence was identified for this variant, so available evidence does not support BS4.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Met	This missense variant is outside the BRCA2 clinically important domains used by the ENIGMA specification, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is at or below the BP1_Strong threshold of 0.1. These findings support BP1_Strong.	cspec spliceai
BP2	N/A	The ENIGMA BRCA2 specification does not use BP2 for this gene framework, so this criterion is not applicable.	cspec
BP3	N/A	The ENIGMA BRCA2 specification does not use BP3 for this gene framework, so this criterion is not applicable.	cspec
BP4	Not met	Although computational predictors do not suggest a damaging effect, BP4 is not applied here because the BRCA2 ENIGMA missense BP4 rule is restricted to variants inside the specified clinically important domains. This variant lies at residue 824, outside those domains, so BP4 is not met and the benign computational evidence is captured by BP1_Strong instead.	cspec spliceai bayesdel revel
BP5	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 0.60 in 2 probands, which is above the ENIGMA BP5 supporting threshold of 0.48. This value falls in the neutral zone and does not support BP5.	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 Likely benign.	cspec clinvar
BP7	Not met	This is a missense variant, and no RNA study demonstrating a benign transcript effect was identified. Available evidence therefore does not support BP7.	cspec spliceai

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