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""
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 | 38 bp |
| Donor Loss (DL) | 0.0 | -256 bp |
| Acceptor Gain (AG) | 0.04 | -8 bp |
| Donor Gain (DG) | 0.0 | 93 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 rule is: "Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor ±1,2), initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease." The evidence for this variant shows a missense change (I2628R), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 rule is: "Strong Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing)." The evidence for this variant shows no previously established pathogenic variant with the same amino acid change (I2628R). Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 rule is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no evidence of a confirmed de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 rule is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." There are no functional studies available for BRCA2 I2628R. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 rule is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (p-value ≤0.05 and OR ≥4)." No case-control data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 rule is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." While I2628R lies within the BRCA2 DNA binding domain (aa2481-3186), there is insufficient evidence regarding absence of benign variation specific to this residue. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 rule is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer) and gnomAD v3.1 (non-cancer)." The evidence for this variant shows it is not present in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, PM3 rule is: "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurring variants in the same gene." There is no evidence of a Fanconi Anemia phenotype or a second BRCA2 variant in trans. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 rule is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." This is a missense change without alteration of protein length. Therefore, this criterion is not applied.
PM5 (Moderate)
According to standard ACMG guidelines, PM5 rule is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." The evidence shows that a different pathogenic missense change at residue 2628 has been reported. Therefore, this criterion is applied at Moderate strength.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 rule is: "Assumed de novo, but without confirmation of paternity and maternity." There is no de novo data for this variant. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 rule is: "Supporting Co-segregation with disease in multiple affected family members." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 rule is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." BRCA2 has both pathogenic and benign missense variants; this rule is not met. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, PP3 rule is: "Supporting Apply PP3 for missense variants inside a clinically important functional domain with BayesDel no-AF ≥0.30 or for predicted splicing (SpliceAI ≥0.2)." The variant lies in the BRCA2 DNA binding domain (aa2481-3186) and has a REVEL score of 0.78 (>0.75). Therefore, this criterion is applied at Supporting strength.
PP4 (Not Applied)
According to VCEP guidelines, PP4 rule is: "Use only for clinical multifactorial likelihood data with LR ≥2.08:1 for breast cancer phenotype." No multifactorial or phenotype data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 rule is: "Reputable source reports variant as pathogenic without available evidence." This variant is not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 rule is: "Stand Alone Filter allele frequency above 0.1% in gnomAD non-founder populations." The variant is absent (MAF=0%). Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 rule is: "Strong Filter allele frequency above 0.01% in gnomAD non-cancer populations." The variant is absent (MAF=0%). Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 rule is: "Applied in absence of Fanconi Anemia phenotype (≥4 healthy individuals)." No healthy adult data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 rule is: "Strong Well-established functional studies show no damaging effect." No functional studies demonstrate lack of damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 rule is: "Strong Lack of segregation in affected members (LR ≤0.05:1)." No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, BP1_Strong rule is: "Silent or in-frame variants outside clinically important domain with no predicted splicing impact." This is a missense variant inside a clinically important domain. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 rule is: "Observed in trans with a pathogenic variant for a dominant disorder." No evidence of trans configuration with a pathogenic variant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 rule is: "In-frame indel in a repetitive region without a known function." This is a missense variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 rule is: "Supporting Missense or in-frame variants inside a clinically important domain with BayesDel no-AF ≤0.18 and SpliceAI ≤0.1." The variant has REVEL 0.78 supporting deleterious impact and SpliceAI minimal impact; it does not meet benign thresholds. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, BP5 rule is: "Use only for co-observation with pathogenic variants in other breast cancer genes with LR ≤0.48:1." No co-observation data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 rule is: "Reputable source reports variant as benign without evidence." This variant is not reported as benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 rule is: "Supporting Silent or intronic variants outside conserved splice sites with no predicted splicing impact." This is a missense variant. Therefore, this criterion is not applied.