NM_000059.3:c.9117+2T>C is a canonical +2 splice donor variant in BRCA2 exon 23, disrupting the GT dinucleotide of the donor splice site. ENIGMA Specification Table 4 assigns PVS1 (RNA) at very strong weight based on confirmed aberrant splicing by RNA assay. The exon encodes residues 2985-3039 within the DNA binding domain, a clinically important functional region where loss of function is an established disease mechanism for hereditary breast and ovarian cancer.1 The variant is absent from gnomAD v2.1 and v4.1 outbred populations, meeting ENIGMA PM2_Supporting (absent from controls). No filter allele frequency data suggest the variant is present in any population database.2 No formal case-control study (PS4), co-segregation analysis (PP1), or clinical-history likelihood ratio (PP4/BP5) meeting ENIGMA quantitative thresholds is available. The variant is not listed in the Li et al. 2020 BRCA2 clinical-history LR table (PMID:31853058). ENIGMA PS3, BS3, BS1, BS2, BS4, and BA1 criteria are not met, and BP1, BP4, BP7, PM1, PM5, PP2, PP5, BP2, BP6 are not applicable under the ENIGMA specification.3 Under ENIGMA Table 3 combining rules, one Very Strong criterion (PVS1) and one Supporting criterion (PM2) is sufficient for a Likely Pathogenic classification.4
BRCA2
Final classification
Likely Pathogenic
BRCA2 c.9117+2T>C · p.?
BRCA2
NM_000059.3:c.9117+2T>C is a canonical +2 splice donor variant in BRCA2 exon 23, disrupting the GT dinucleotide of the donor splice site. ENIGMA Specification Table 4 assigns PVS1 (RNA) at very strong weight based on confirmed aberrant splicing by RNA assay. The exon encodes residues 2985-3039 within the DNA binding domain, a clinically important functional region where loss of function is an established disease mechanism for hereditary breast and ovarian cancer.
ENIGMA BRCA1/BRCA2 VCEP Specification v1.2.0, Table 3 combination rules applied to adjudicated criteria. One Very Strong criterion (PVS1) plus one Supporting criterion (PM2) satisfies the Likely Pathogenic threshold under Table 3: [1 Very Strong + 1 Supporting -> Likely Pathogenic]. ENIGMA point system yields 8 + 1 = 9 points, within the Likely Pathogenic range (6-9). No benign criteria are met, so no conflicting evidence.
Classification rationale
PVS1PM2
Likely Pathogenic
BRCA2 c.9117+2T>C
PVS1 + PM2
→
Likely Pathogenic
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 267714)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.321175.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
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.
Literature · 20 PMIDs triaged · 8 high-priority
20papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
23918944 ↗
splicing rna
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familia
BP7PP3PP5PS4PVS1
15604628 ↗
case observation
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in
PP5PS4
17392385 ↗
case observation
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
New evidence on breast Magnetic Resonance Imaging (MRI) screening has become available since the American Cancer Society (ACS) last issued guidelines for the early detection of breast cancer in 2003. A guideline panel has reviewed this evidence and developed new recommendations for women at different defined levels of risk. Screening MRI is recommended for women with an approximately 20-25% or gre
PP5PS4
17508274 ↗
case observation
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial and ethical implications of identifying at-risk individuals for hereditary breast and ovarian cancer (HBOC) through cancer risk assessment, with or without genetic susceptibility testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors' Familial Cancer
PP5PS4
19305347 ↗
case observation
ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.
Hereditary breast and ovarian cancer syndrome is an inherited cancer-susceptibility syndrome. The hallmarks of this syndrome are multiple family members with breast cancer or ovarian cancer or both, the presence of both breast cancer and ovarian cancer in a single individual, and early age of breast cancer onset. Clinical genetic testing for gene mutations allows physicians to more precisely ident
PP5PS4
20065170 ↗
case observation
American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
PP5PS4
23188549 ↗
case observation
NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
The purpose of this document is to present a current and comprehensive set of practice recommendations for effective genetic cancer risk assessment, counseling and testing for hereditary breast and ovarian cancer. The intended audience is genetic counselors and other health professionals who care for individuals with, or at increased risk of, hereditary breast and/or ovarian cancer.
PP5PS4
Sources & reference links