Variant classification summary

NM_000059.4:c.1644G>A

BRCA2 · NP_000050.3:p.(Gln548=) · NM_000059.4

GRCh37: chr13:32907259 G>A · GRCh38: chr13:32333122 G>A

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP1 strong benign BP6 supporting benign

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Gln548=)

gnomAD AF

5.018444331822017e-05 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BP1 strong benign is met for an out-of-domain synonymous variant with SpliceAI maximum delta 0.003.

2

Likely Benign: BP6 supporting benign is met from the ENIGMA Expert Panel's Benign ClinVar classification.

Final determination: Under ENIGMA BRCA2 VCEP Version 1.2 Table 3, one Strong benign criterion plus one Supporting benign criterion yields Likely Benign.

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	Not applicable: the exon 10 c.1644G>A synonymous SNV preserves p.Gln548 and is not among the VCEP-defined null variant types eligible for PVS1.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 cspec
PS1	Not assessed	Not assessed: no VCEP-listed pathogenic or likely pathogenic comparator with the same protein or splicing consequence was available.	vcep_specifications_v1_2_2024_11_18
PS2	N/A	Not applicable: the VCEP explicitly says "Do not use" because de novo occurrences lack calibrated predictive capacity for BRCA1/2-related cancers.	vcep_specifications_v1_2_2024_11_18
PS3	Not assessed	Not assessed: no variant-specific calibrated functional assay entry or damaging-effect result was found for c.1644G>A (p.Gln548=).	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not assessed	Not assessed: no exact-variant case-control counts, odds ratio, p-value, or confidence interval were found to evaluate the ENIGMA PS4 thresholds.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:23188549 PMID:28392550 PMID:28726806
PM1	N/A	Not applicable: ENIGMA says PM1 is not used for BRCA2 and considers it part of PP3/BP4.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2	Not assessed	Not assessed: required non-cancer gnomAD absence and regional depth at least 25 are unavailable, while available all-comers data show the variant is present.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no documented Fanconi Anemia phenotype, qualifying BRCA2 co-occurring pathogenic variant, phase information, or PM3 points are available for c.1644G>A.	cspec
PM4	N/A	Not applicable: p.Gln548= causes no protein-length change, while the VCEP limits PM4 to in-frame indels or stop-loss variants and says not to use it.	vcep_specifications_v1_2_2024_11_18 cspec
PM5	N/A	Not applicable: the variant is synonymous, while ENIGMA PM5 is not used for missense changes and is repurposed only for PTC variants.	vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Not applicable: the VCEP explicitly says "Do not use" because de novo occurrences lack calibrated predictive capacity for BRCA1/2-related cancers.	vcep_specifications_v1_2_2024_11_18
PP1	Not assessed	Not assessed: no quantitative co-segregation likelihood ratio or affected-family genotype data is available to compare with the PP1 threshold of LR ≥2.08:1.	vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PP2	N/A	Not applicable: ENIGMA says PP2 is not used because BRCA2 has a high frequency of benign missense variants.	vcep_specifications_v1_2_2024_11_18
PP3	Not met	Not met: SpliceAI maximum delta score is 0.003, below the ENIGMA PP3 threshold of 0.2 for predicted splicing in silent variants.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18
PP4	Not assessed	Not assessed: the exact variant has no available ENIGMA multifactorial clinical likelihood ratio for comparison with the PP4 LR thresholds.	cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine vcep_pmid_17924331_easton_2007_ajhg vcep_pmid_31853058_methods_supplement
PP5	N/A	Not applicable: the ENIGMA BRCA2 VCEP explicitly marks PP5 as Not Applicable.	cspec
BA1	Not assessed	Not assessed: required non-cancer gnomAD FAF and regional read-depth data are unavailable, so the VCEP's BA1 threshold cannot be applied.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: required non-cancer gnomAD FAF is unavailable, so neither VCEP BS1 frequency interval can be applied.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying phenotyped healthy-adult observation is available, and the VCEP excludes gnomAD frequency observations from BS2 scoring.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific calibrated functional assay entry or no-damaging-effect result was found for c.1644G>A (p.Gln548=).	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4	Not assessed	Not assessed: no quantitative non-segregation likelihood ratio or affected-family genotype data is available to compare with the BS4 threshold of LR ≤0.48:1.	vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Met	Met at strong strength: the variant is silent, lies outside aa 10–40 and 2481–3186, and SpliceAI max delta is 0.003.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2	N/A	Not applicable: the BRCA2 VCEP says BP2 should not be used except in the context of BS2.	cspec
BP3	N/A	Not applicable: this synonymous SNV is not an in-frame deletion or insertion in a repetitive region, and the VCEP explicitly says BP3 is not used.	vcep_specifications_v1_2_2024_11_18 cspec
BP4	N/A	Not applicable: p.Gln548= is outside ENIGMA's defined BRCA2 domains at aa 10-40 and aa 2481-3186, so BP4's silent-variant path does not apply.	cspec spliceai
BP5	Not assessed	Not assessed: no exact-variant multifactorial LR is available to test against the ENIGMA BP5 <=0.48 supporting threshold.	cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine vcep_pmid_17924331_easton_2007_ajhg vcep_pmid_31853058_methods_supplement
BP6	Met	Not applicable: the ENIGMA BRCA2 VCEP explicitly marks BP6 as Not Applicable.	cspec clinvar
BP7	N/A	Not applicable: BP7 requires a silent variant inside an ENIGMA-defined functional domain with BP4 met, but p.Gln548= lies outside those domains.	cspec

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