0%
complete
Final classification
Likely Benign
BP4BP7
BRCA2
c.7617+16C>T
p.?
unknown · exon 15i
Gene context NCBI Gene ↗ OncoKB ↗

BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.

This variant

BRCA2 is a tumor-suppressor gene in which loss-of-function changes predispose to hereditary breast and ovarian cancer, making splice-disrupting alterations clinically significant. This intronic +16 variant is classified Likely Benign, indicating it is not expected to disrupt BRCA2's DNA-repair function or meaningfully elevate cancer risk.

Transcript
NM_000059.4
HGVS · transcript:coding
NM_000059.4:c.7617+16C>T
GRCh38
chr13:32356625 C>T
GRCh37
chr13:32930762 C>T
Under the ENIGMA BRCA2 v1.2 Table 3 framework, two Supporting (Benign) criteria (BP4 and BP7) are met, satisfying the combination for Likely Benign.
Classification rationale
BP4BP7 Likely Benign
BRCA2 c.7617+16C>T unknown · exon 15i

BP4 (Supporting): SpliceAI max delta 0.018 predicts no significant splice impact, below the 0.1 threshold. BP7 (Supporting): the +16 intronic position meets the positional benignity rule (at or beyond +7/-21) conditional on BP4. Synthesis: two Supporting (Benign) criteria satisfy the ENIGMA BRCA2 v1.2 combination rule, giving a final classification of Likely Benign.

BP4 + BP7 → Likely Benign
Gene diagram · NM_000059.4 · variants mapped to exon structure
BRCA2 NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
BP4 supporting Benign
Met (Supporting): SpliceAI max delta 0.018 is below the 0.1 BP4 threshold for this intronic +16 variant.
ENIGMA BRCA2 v1.2 specifies BP4_Supporting for intronic variants outside native donor and acceptor +/-1,2 positions with SpliceAI <=0.1.SpliceAI for NM_000059.4:c.7617+16C>T reports a maximum delta score of 0.018.
cspec ↗spliceai ↗
BP7 supporting Benign
Met (Supporting): position +16 satisfies BP7's intronic positional rule (at or beyond +7/-21), conditional on BP4.
ENIGMA BRCA2 v1.2 specifies BP7_Supporting for intronic variants at or beyond positions +7/-21 if BP4 is met.NM_000059.4:c.7617+16C>T is 16 nucleotides into the intron and SpliceAI maximum delta is 0.018, which meets the linked BP4 requirement.
cspec ↗spliceai ↗
Assessed · not applied · 7 not met · 10 not assessed
Pathogenic
PVS1 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).
PS1 Not met: intronic variant has no protein change (p.?), and no documented pathogenic change matches its predicted protein or splice effect.
PS3 Not assessed: insufficient evidence was available, with no validated variant-specific functional assay result for this variant.
PS4 Not assessed: no ethnicity- and country-matched case-control study met the required thresholds (p<=0.05, OR>=4).
PM2 Not assessed: the required gnomAD v3.1 result was unavailable, and the variant is not globally absent (gnomAD v4.1 AF 2.48e-6).
PM3 Not assessed: no Fanconi anemia phenotype, second BRCA2 variant, or phase information was available to assess.
PP1 Not assessed: no family-member genotypes or co-segregation data were available.
PP3 Not met: SpliceAI max delta 0.018 is far below the >=0.2 threshold required for PP3.
PP4 Not assessed: no combined multifactorial likelihood ratio toward pathogenicity was available.
PP5 Not met: the ClinVar entry (ID 531528) has only a single-laboratory Likely benign submission, with no expert-panel support.
Benign
BA1 Not met: absent from gnomAD v2.1, with gnomAD v4.1 AF 2.48e-6, far below the required FAF >0.001 (0.1%).
BS1 Not met: gnomAD grpmax FAF 3.65e-6 falls below the BS1 supporting threshold (>2.0e-5); no qualifying v2.1/v3.1 observation.
BS2 Not assessed: no proband phenotype, clinical findings, or BS2 point calculation was available.
BS3 Not assessed: insufficient evidence was available, with no validated variant-specific functional assay result.
BS4 Not assessed: no family genotypes or non-segregation evidence was available.
BP5 Not assessed: no combined multifactorial likelihood ratio against pathogenicity was available.
BP6 Not met: the only ClinVar submission (ID 531528) is a single-laboratory Likely benign assertion, not an expert panel.
N/A · 9 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP1 · BP2 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.48041e-06; MAF= 0.00025%, 4/1612638 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37861e-05; MAF= 0.00338%, 1/29598 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025% · 4 / 1,612,638
0 hom · FAF 0.00037%
Ashkenazi Jewish
1 / 29,598
0.0034%
South Asian
2 / 91,050
0.0022%
Remaining individuals
1 / 62,440
0.0016%
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, African/African American, European (non-Finnish))
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 531528)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
8Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Triaged references · 6 PMIDs not cited in assessment
18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR
19305347 ↗ ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. CLINVAR
25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR
26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR
31429903 ↗ Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR