NM_000059.4:c.4494T>A (p.Gly1498=) is a synonymous variant in BRCA2 exon 11. BP1_Strong is met: the variant is a silent substitution outside the clinically important functional domains (aa 10-40 and 2481-3186) with no predicted splicing impact (SpliceAI max delta=0.00).1 BS1_Supporting is met: gnomAD v4.1 filter allele frequency is 3.34e-05 (0.0033%), exceeding the 0.002% threshold for BS1_Supporting under ENIGMA rules.2 PVS1, PS3, PM2, PM5, PP3, PP4, BA1, BS3, BS4, and BP5 are not met or not applicable. The variant is present in gnomAD, lacks functional evidence of pathogenicity, and has no segregation or case-control data.3 ClinVar expert panel (ENIGMA) classifies this variant as Likely Benign (ClinVar ID: 184407), consistent with the criteria assessment.4 Applying ENIGMA Table 3 point system: BP1_Strong = -4 points, BS1_Supporting = -1 point, total = -5 points, which falls in the Likely Benign range (-6 to -2). The combination of one Strong (Benign) and one Supporting (Benign) criterion satisfies the ENIGMA Likely Benign classification rule.5 Exploratory evidence suggests c.4494T>A exhibits normal splicing in a minigene assay (PMID:28608497), which, if verified, would add BP7_Strong (RNA), further strengthening the benign classification.
BRCA2
Final classification
Likely Benign
BRCA2 c.4494T>A · p.Gly1498=
BRCA2
NM_000059.4:c.4494T>A (p.Gly1498=) is a synonymous variant in BRCA2 exon 11.
ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3 classification framework applied. One Strong (Benign) criterion (BP1_Strong) and one Supporting (Benign) criterion (BS1_Supporting) are met, satisfying the ENIGMA Likely Benign combination rule. ENIGMA point system yields -5 points (BP1_Strong = -4, BS1_Supporting = -1), falling in the Likely Benign range (-6 to -2). No pathogenic criteria are met, so no conflicting-evidence point calculation is required.
Classification rationale
BS1BP1BP6
Likely Benign
BRCA2 c.4494T>A
BS1 + BP1 + BP6
→
Likely Benign
3
gnomad_v2 ↗gnomad_v4 ↗spliceai ↗vcep_specifications_table9_v1_2_2024_11_18
5
cspec ↗
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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 benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.22278e-05; MAF= 0.00322%, 52/1613516 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.32349e-05; MAF= 0.00432%, 51/1179602 alleles, homozygotes = 0); grpmax FAF= 3.342e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.99692e-05; MAF= 0.00200%, 5/250386 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.42642e-05; MAF= 0.00443%, 5/112958 alleles, homozygotes = 0); grpmax FAF= 1.694e-05.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0032%
· 52 / 1,613,516
0 hom · FAF 0.0033%
0 hom · FAF 0.0033%
European (non-Finnish) 51 / 1,179,602 |
0.0043% |
African/African American 1 / 74,922 |
0.0013% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.002%
· 5 / 250,386
0 hom · FAF 0.0017%
0 hom · FAF 0.0017%
European (non-Finnish) 5 / 112,958 |
0.0044% |
+ 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.
ClinVar
This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 184407)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
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
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
17508274 ↗
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR