Variant classification summary

NM_000059.4:c.7617+16C>T

BRCA2 · NP_000050.3:p.? · NM_000059.4

GRCh37: chr13:32930762 C>T · GRCh38: chr13:32356625 C>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP4 supporting BP7 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.?

gnomAD AF

2.480407878271503e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): SpliceAI max delta 0.018 predicts no significant splice impact, below the 0.1 threshold.

2

BP7 (Supporting): the +16 intronic position meets the positional benignity rule (at or beyond +7/-21) conditional on BP4.

3

Synthesis: two Supporting (Benign) criteria satisfy the ENIGMA BRCA2 v1.2 combination rule, giving a final classification of Likely Benign.

Final determination: Under ENIGMA BRCA2 v1.2 Table 3, at least two Supporting (Benign) criteria result in 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	Not met: intronic +16 substitution is not a null or canonical +/-1,2 splice variant, and SpliceAI predicts no splice impact (max delta 0.018).	cspec spliceai
PS1	Not met	Not met: intronic variant has no protein change (p.?), and no documented pathogenic change matches its predicted protein or splice effect.	cspec spliceai
PS2	N/A	Not applicable: the ENIGMA BRCA2 v1.2 specification designates PS2 (de novo evidence) as not applicable.	cspec
PS3	Not assessed	Not assessed: insufficient evidence was available, with no validated variant-specific functional assay result for this variant.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	Not assessed: no ethnicity- and country-matched case-control study met the required thresholds (p<=0.05, OR>=4).	cspec
PM1	N/A	Not applicable: this intronic variant has no protein residue to map to BRCA2's critical functional domains.	cspec
PM2	Not assessed	Not assessed: the required gnomAD v3.1 result was unavailable, and the variant is not globally absent (gnomAD v4.1 AF 2.48e-6).	cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no Fanconi anemia phenotype, second BRCA2 variant, or phase information was available to assess.	cspec gnomad_v2 gnomad_v4
PM4	N/A	Not applicable: ENIGMA BRCA2 v1.2 marks PM4 not applicable, and no in-frame protein-length change applies.	cspec
PM5	N/A	Not applicable: PM5 is restricted to protein-termination-codon variants; this intronic variant is not a PTC.	cspec
PM6	N/A	Not applicable: de novo evidence (PM6) is not calibrated for BRCA1/2-related cancers under ENIGMA v1.2.	cspec
PP1	Not assessed	Not assessed: no family-member genotypes or co-segregation data were available.	cspec
PP2	N/A	Not applicable: ENIGMA BRCA2 v1.2 marks PP2 not applicable, and the variant is intronic rather than missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.018 is far below the >=0.2 threshold required for PP3.	cspec spliceai
PP4	Not assessed	Not assessed: no combined multifactorial likelihood ratio toward pathogenicity was available.	cspec PMID:31853058
PP5	Not met	Not met: the ClinVar entry (ID 531528) has only a single-laboratory Likely benign submission, with no expert-panel support.	clinvar cspec
BA1	Not met	Not met: absent from gnomAD v2.1, with gnomAD v4.1 AF 2.48e-6, far below the required FAF >0.001 (0.1%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD grpmax FAF 3.65e-6 falls below the BS1 supporting threshold (>2.0e-5); no qualifying v2.1/v3.1 observation.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no proband phenotype, clinical findings, or BS2 point calculation was available.	cspec
BS3	Not assessed	Not assessed: insufficient evidence was available, with no validated variant-specific functional assay result.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	Not assessed: no family genotypes or non-segregation evidence was available.	cspec
BP1	N/A	Not applicable: BP1 does not cover intronic variants; this is an intronic substitution.	cspec spliceai
BP2	N/A	Not applicable: the ENIGMA BRCA2 v1.2 specification designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: this is a single-nucleotide intronic substitution, not an in-frame indel in a repetitive region.	cspec
BP4	Met	Met (Supporting): SpliceAI max delta 0.018 is below the 0.1 BP4 threshold for this intronic +16 variant.	cspec spliceai
BP5	Not assessed	Not assessed: no combined multifactorial likelihood ratio against pathogenicity was available.	cspec PMID:31853058
BP6	Not met	Not met: the only ClinVar submission (ID 531528) is a single-laboratory Likely benign assertion, not an expert panel.	clinvar cspec
BP7	Met	Met (Supporting): position +16 satisfies BP7's intronic positional rule (at or beyond +7/-21), conditional on BP4.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.