Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000059.4 | MANE Select | 11954 nt | 200–10456 |
| NM_000059.2 | Alternative | 11386 nt | 228–10484 |
| NM_000059.3 | RefSeq Select | 11386 nt | 228–10484 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -103 bp |
| Donor Loss (DL) | 0.0 | 40 bp |
| Acceptor Gain (AG) | 0.0 | -408 bp |
| Donor Gain (DG) | 0.04 | -60 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines for PVS1: "Very Strong Null variant (nonsense, frameshift, splice site ... loss of function) in a gene where LOF is a known mechanism of disease." The evidence shows this is a missense variant (P2589T), not a null variant. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to VCEP guidelines for PS1: "Strong Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant has the same amino acid change." There is no previously established pathogenic variant with P2589T. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines for PS2: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no evidence of de novo occurrence. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines for PS3: "Well-established in vitro or in vivo functional studies supportive of a damaging effect." No functional studies exist for this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines for PS4: "Prevalence in affected individuals is significantly increased compared to controls (OR ≥4, p ≤0.05)." No case-control data are available. Therefore, PS4 is not applied.
PM1 (Moderate)
According to standard ACMG guidelines for PM1: "Located in a mutational hot spot and/or critical functional domain without benign variation (Moderate)." The variant P2589T lies within the BRCA2 DNA binding domain (aa2481–3186), a critical functional region. Therefore, PM1 is applied at Moderate strength.
PM2 (Supporting)
According to VCEP guidelines for PM2: "Supporting Absent from controls in gnomAD v2.1 (non-cancer exome) and gnomAD v3.1 (non-cancer)." The variant is extremely rare (MAF = 0.000398%, 1/251418 alleles) and absent in non-cancer subset. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines for PM3: "Apply for BRCA2-related Fanconi Anemia phenotype with co-occurrence of variants." No Fanconi Anemia phenotype or co-occurrence data are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines for PM4: "Protein length changes due to in-frame indels or stop-loss variants." This is a missense variant. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines for PM5: "A different amino acid change at the same codon is pathogenic (Moderate)." No other pathogenic change at codon 2589 is reported. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines for PM6: "Assumed de novo without confirmation of paternity and maternity." No de novo data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines for PP1: "Co-segregation with disease in multiple affected family members (Supporting to Strong)." No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines for PP2: "Missense variant in a gene with a low rate of benign missense variation and pathogenic missense is common." BRCA2 has both benign and pathogenic missense variants; no clear evidence supports PP2. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines for PP3: "Supporting predicted impact via protein change (BayesDel ≥0.30) or splicing (SpliceAI ≥0.2)." In silico predictions are mixed and SpliceAI = 0.04. Thus, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines for PP4: "Phenotype-based multifactorial likelihood data required for breast cancer." No such data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines for PP5: "Reputable source classifies variant as pathogenic." ClinVar reports this variant as VUS. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines for BA1: "Filter allele frequency >0.001 in gnomAD non-cancer indicates stand-alone benign." The variant frequency (0.00000398) is below this threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines for BS1: "Filter allele frequency >0.0001 (Strong) or >0.00002 (Supporting) and ≤0.0001." The variant frequency (0.00000398) is below both thresholds. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines for BS2: "Observed in healthy adults without recessive disease phenotype (Fanconi Anemia)." No phenotype data on carriers are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: "Well-established functional studies show no damaging effect." No such studies exist. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines for BS4: "Lack of segregation in affected family members." No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to VCEP guidelines for BP1: "Missense variant outside clinically important domain and no splicing impact." This variant lies inside the DNA binding domain. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines for BP2: "Observed in trans with a pathogenic variant for a dominant disorder." No co-occurrence data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines for BP3: "In-frame indels in repetitive regions without known function." This is a missense variant. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines for BP4: "Supporting No predicted impact via protein change or splicing (BayesDel ≤0.18 and SpliceAI ≤0.1)." Computational evidence is mixed with SpliceAI = 0.04 and overall in silico favoring benign. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines for BP5: "Cases with pathogenic variants in other breast-ovarian cancer genes without specific phenotype." No such co-observations are reported. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines for BP6: "Reputable source classifies variant as benign." ClinVar reports this variant as VUS. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines for BP7: "Silent or intronic variants outside splice sites with no impact." This variant is missense. Therefore, BP7 is not applied.