Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_007294.2 | Alternative | 7191 nt | 201–5792 |
| NM_007294.3 | RefSeq Select | 7224 nt | 233–5824 |
| NM_007294.4 | MANE Select | 7088 nt | 114–5705 |
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 | -425 bp |
| Donor Loss (DL) | 0.0 | 37 bp |
| Acceptor Gain (AG) | 0.0 | 340 bp |
| Donor Gain (DG) | 0.01 | -13 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: '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 synonymous (silent) change with no predicted truncation or LOF. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows no amino acid change (F989=) and no matching known pathogenic 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.' There is no de novo or pedigree information available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect.' No functional assay data are available for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (p ≤0.05, OR ≥4).' No case-control or affected cohort data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well‐established functional domain without benign variation.' This variant is a synonymous change outside of any clinically important BRCA1 functional domain. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 is: 'Supporting: Absent from controls in an outbred population (gnomAD v2.1 non-cancer and v3.1 non-cancer).' The evidence for this variant shows it is present at low frequency in gnomAD (MAF=0.000399%), so it is not absent. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'For patient with phenotype consistent with BRCA1‐ or BRCA2‐related Fanconi Anemia and co‐occurrence of variants in trans.' No Fanconi Anemia phenotype or trans variant data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in‐frame deletions/insertions.' This variant is synonymous with no length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Protein termination codon variant in an exon where a different proven pathogenic PTC variant has been seen before.' This variant is not a termination codon change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity.' No such data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: '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: 'Missense variant in a gene with low rate of benign missense variants.' This variant is synonymous, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Supporting: In silico predictions of deleterious effect on protein or splicing (BayesDel no-AF ≥0.28 or SpliceAI ≥0.2).' The evidence shows SpliceAI score of 0.01 and CADD of -0.10, indicating no deleterious prediction. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: 'Supporting: Specific phenotype or family history for disease with high heterogeneity.' No specific familial or clinical data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic.' This variant is not found in ClinVar or other expert sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: Filter allele frequency above 0.1% in gnomAD non‐cancer.' The variant frequency (0.000399%) is below 0.1%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong: Filter allele frequency above 0.01%.' The variant frequency (0.000399%) is below 0.01%. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed in healthy individuals in absence of recessive phenotype.' Population data alone without phenotype confirmation do not meet BS2 criteria. Therefore, BS2 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 assays have been performed. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected members.' No segregation analysis is available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 is: 'Strong: Silent or in‐frame variant outside functional domain with no splicing predicted.' This variant is silent but VCEP BP1 is defined for missense/in‐frame variants; synonymous classification falls under BP7 or BP4. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant in a disorder for which two variants are needed.' No such co‐occurrence data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function.' Not applicable to a synonymous SNV. Therefore, BP3 is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).' The evidence for this variant shows a CADD score of -0.10 and SpliceAI maximum score of 0.01 indicating no predicted impact. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: 'Supporting: Co‐observation with pathogenic variant in another gene without specific phenotype.' No such co‐occurrence data are present. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign.' No external expert classifications are available. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence or create a new splice site.' While computational evidence shows no splice impact, VCEP guidelines do not define BP7 for silent variants outside functional domains without mRNA assay data. Therefore, BP7 is not applied.