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
OpenMissense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
"This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance (1 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 | -204 bp |
| Donor Loss (DL) | 0.01 | 8 bp |
| Acceptor Gain (AG) | 0.0 | -180 bp |
| Donor Gain (DG) | 0.0 | 495 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor ±1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease." The evidence for this variant shows it is a missense change (I2278S), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong: same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no previously established pathogenic I2278S variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong: well-established in vitro or in vivo functional studies supportive of a damaging effect." No functional assay data exist for I2278S. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong: prevalence of variant in affected individuals is significantly increased compared to controls (p ≤0.05, OR ≥4)." No case-control data exist. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Moderate: variant located in a mutational hot spot or well-studied functional domain without benign variation." I2278S lies outside the defined PALB2 binding domain (aa10-40) and DNA-binding domain (aa2481-3186). Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: absent from controls in gnomAD v2.1 (non-cancer) and v3.1 (non-cancer), read depth ≥25." The evidence for this variant shows it is absent from gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Supporting/Moderate/Strong: observed in trans with a pathogenic variant in patients with BRCA2-related Fanconi Anemia." No FA or trans compound heterozygosity data exist. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame indel or stop-loss that is not predicted to impact splicing." This is a missense change, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: "Moderate: novel missense change at an amino acid where a different missense change determined to be pathogenic has been seen." The evidence for this variant shows that another pathogenic missense at residue I2278 has been reported. Therefore, this criterion is applied at Moderate strength.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Supporting: assumed de novo, without confirmation of paternity/maternity." No such data exist. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong: 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, the rule for PP2 is: "Supporting: missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." BRCA2 does not have a low rate of benign missense variation, and many missense variants are VUS. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting: computational evidence of impact (BayesDel no-AF ≥0.30 or SpliceAI ≥0.2)." In silico tools (CADD, PolyPhen, REVEL 0.31) and SpliceAI (0.01) predict no impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting/Moderate/Strong: phenotype specificity in BRCA2 disorders using multifactorial likelihood data." No phenotype or multifactorial data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: reputable source reports variant as pathogenic without available evidence." This is discouraged and no such reports exist. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: allele frequency >0.1% in gnomAD non-cancer populations." The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: filter allele frequency >0.01% in gnomAD non-cancer populations." The variant is absent. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Supporting/Moderate/Strong: observed in healthy adults without Fanconi Anemia features." No such data exist. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: well-established functional studies show no damaging effect." No functional data exist. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong/Moderate/Supporting: lack of segregation in affected family members." No segregation data exist. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines, the rule for BP1 is: "Strong: missense variant outside clinically important functional domains (aa10-40 or aa2481-3186) and no splicing impact (SpliceAI ≤0.1)." I2278S lies outside those domains and SpliceAI=0.01. Therefore, this criterion is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Supporting: observed in trans with a pathogenic variant for a fully penetrant dominant disorder." No such data exist. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: in-frame indels in repetitive regions without known function." This is a missense variant, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: missense inside a functional domain with no impact predicted (BayesDel ≤0.18 and SpliceAI ≤0.1)." The variant is outside defined domains. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting/Moderate/Strong: co-observation with pathogenic variants in other genes without specific phenotype." No such data exist. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: reputable source reports variant as benign without available evidence." No such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: silent or intronic variants outside splice sites with no splicing impact after BP4 met." This variant is missense. Therefore, this criterion is not applied.