The BRCA2 c.9257-18C>A variant has been reported in ClinVar, where most clinical laboratory submissions classify it as likely benign or benign, although one submission remains uncertain.1 This variant is present at very low frequency in population databases, with 3/240598 alleles in gnomAD v2.1 and 10/1607522 alleles in gnomAD v4.1; these frequencies are below the BS1 and BA1 thresholds but do not meet the PM2 absence requirement.2 In a published RNA study, RT-PCR showed no aberrant splicing for this variant, and the BRCA multifactorial splicing dataset also records no aberration, which is consistent with no measurable splice disruption.3 Computational splicing prediction supports a benign interpretation, with SpliceAI showing a maximum delta score of 0.01, below the BRCA2 BP4 threshold of 0.1 and well below the PP3 threshold of 0.2.4
BRCA2
Final classification
Unclassified
BRCA2 c.9257-18C>A · p.?
BRCA2
The BRCA2 c.9257-18C>A variant has been reported in ClinVar, where most clinical laboratory submissions classify it as likely benign or benign, although one submission remains uncertain.
Classification rationale
BP4
Unclassified
BRCA2 c.9257-18C>A
· exon NC_000013.10
BP4
→
Unclassified
3
vcep_humu_40_1557_s001PMID:16619214
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 14 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
This intronic variant is outside the native donor and acceptor splice sites and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, which is below the BRCA2 BP4 threshold of 0.1. This supports a benign computational interpretation.
Variant position c.9257-18 is not at ±12.SpliceAI max delta score 0.01.
Assessed · not applied
Pathogenic
PVS1
This intronic variant is at c.9257-18, outside the canonical ±1,2 splice consensus positions used for BRCA2 PVS1 null-variant application, and SpliceAI does not predict a splice-disrupting effect (max delta score 0.01).
PS1
No published comparator variant with the same proven splicing effect was identified to support PS1 for this intronic BRCA2 variant.
PS4
No case-control study showing significant enrichment of this variant in affected individuals compared with controls was identified.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified that this variant was observed in trans with a pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia features.
PP1
No quantitative segregation data were identified for this variant.
PP3
Computational evidence does not support a splice-altering effect.
PP4
No qualifying BRCA2 clinical-history likelihood ratio from the ENIGMA-approved LR resource was identified for this variant.
Benign
BA1
Population frequency is well below the BRCA2 BA1 threshold.
BS1
Population frequency is below the BRCA2 BS1 threshold.
BS2
No data were identified showing this variant in a context that would score BS2 under the BRCA2 Fanconi anemia framework.
BS4
No quantitative non-segregation data were identified for this variant.
BP5
No qualifying BRCA2 clinical-history likelihood ratio against pathogenicity was identified for this variant in the ENIGMA-approved LR resource.
BP7
A published RT-PCR study reported no aberrant splicing for this variant, and the multifactorial splicing dataset also lists no aberration; however, the variant is at c.9257-18, which is not in the intronic position range automatically eligible for BP7 from BP4 alone under the BRCA2 rule, and no explicit ENIGMA BP7 RNA calibration assignment was retrieved for this exact variant.
N/A · 13
PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BS3 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.22075e-06; MAF= 0.00062%, 10/1607522 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.21366e-05; MAF= 0.00221%, 2/90348 alleles, homozygotes = 0); grpmax FAF= 3.68e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.24689e-05; MAF= 0.00125%, 3/240598 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.78686e-05; MAF= 0.00279%, 3/107648 alleles, homozygotes = 0); grpmax FAF= 7.41e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00062%
· 10 / 1,607,522
0 hom · FAF 0.00037%
0 hom · FAF 0.00037%
South Asian 2 / 90,348 |
0.0022% |
European (non-Finnish) 8 / 1,175,998 |
0.00068% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 3 / 240,598
0 hom · FAF 0.00074%
0 hom · FAF 0.00074%
European (non-Finnish) 3 / 107,648 |
0.0028% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
COSMIC
Somatic evidence
COSMIC
In progress — evidence not uploaded yet.
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
16619214 ↗
Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression.
CLINVAR
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
25382762 ↗
Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
12692171 ↗
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR