Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_007294.4 | MANE Select | 7088 nt | 114–5705 |
| NM_007294.2 | Alternative | 7191 nt | 201–5792 |
| NM_007294.3 | RefSeq Select | 7224 nt | 233–5824 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Likely Benign (1 clinical laboratories) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel."
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 | -102 bp |
| Donor Loss (DL) | 0.0 | 152 bp |
| Acceptor Gain (AG) | 0.0 | 376 bp |
| Donor Gain (DG) | 0.0 | -184 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies to null variants (nonsense, frameshift, canonical ±1,2 splice, initiation codon, exon deletions) in a gene where loss of function is a known mechanism. The rule for PVS1 is: 'Very Strong Null variant ...'. The evidence for this variant shows it is a synonymous change (N609=) with no impact on protein sequence. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies to predicted missense substitutions where a previously classified pathogenic variant yields the same amino acid change. The rule for PS1 is: 'Strong: predicted missense substitution matching a known pathogenic missense change'. The evidence for this variant shows it is a synonymous change (no amino acid substitution). Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 applies to confirmed de novo variants (maternity and paternity confirmed). The rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows no parental testing data. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 applies when well-established in vitro or in vivo functional studies support a damaging effect. The rule for PS3 is: 'Well-established functional studies supportive of a damaging effect'. The evidence for this variant shows no functional studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 applies when the variant is significantly enriched in affected individuals compared to controls (p≤0.05, OR≥4). The rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared to controls'. The evidence for this variant shows no case-control or affected individual data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to variants located in established mutational hotspots or critical functional domains without benign variation. The rule for PM1 is: 'Moderate: variant located in mutational hotspot or critical domain'. The evidence for this variant shows it is a silent change at codon 609, outside all clinically important BRCA1 domains (RING 2–101, coiled-coil 1391–1424, BRCT repeats 1650–1857). Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, PM2_Supporting requires the variant to be absent from controls in gnomAD non-cancer. The rule for PM2 is: 'Supporting: absent from controls in an outbred population'. The evidence for this variant shows it is present in gnomAD at MAF=0.000797%. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP guidelines, PM3 applies for co-occurrence of variants in BRCA1-related Fanconi anemia patients. The rule for PM3 is: 'Apply for patient with FA phenotype and co-occurring variants in the same gene'. The evidence for this variant shows no FA phenotype or co-occurrence data. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels or stop-loss. The rule for PM4 is: 'Protein length changes as a result of in-frame indels or stop-loss variants'. The evidence for this variant shows it is a synonymous SNV with no change in protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 applies to novel missense changes at an amino acid residue where a different missense change is pathogenic. The rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense exists'. The evidence for this variant shows it is synonymous, not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation of parentage. The rule for PM6 is: 'Assumed de novo in a patient with the disease and no family history'. The evidence for this variant shows no parental or de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 applies to co-segregation with disease in multiple affected family members. The rule for PP1 is: 'Supporting: co-segregation with disease in multiple affected family members'. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low rates of benign missense variation. The rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variation'. The evidence for this variant shows it is synonymous, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 applies to predicted splicing impact (SpliceAI≥0.2) or deleterious protein impact in domain (BayesDel≥0.28). The rule for PP3 is: 'Supporting for predicted splicing impact or protein impact in functional domain'. The evidence for this variant shows SpliceAI predicts no impact (all scores <0.2) and no protein change. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 applies to combined clinical evidence (multifactorial LR) for a characteristic phenotype. The rule for PP4 is: 'Use to capture combined LR towards pathogenicity based on multifactorial clinical data'. The evidence for this variant shows no clinical phenotype or multifactorial data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic without available evidence. The rule for PP5 is: 'Reputable source reports variant as pathogenic but evidence not available'. The evidence for this variant shows no such pathogenic reports. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies when filter allele frequency exceeds 0.1% in gnomAD non-cancer. The rule for BA1 is: 'Stand Alone: FAF >0.001'. The evidence for this variant shows MAF=0.00000797 (0.000797%), below the threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies when filter allele frequency exceeds 0.01% in gnomAD non-cancer. The rule for BS1 is: 'Strong: FAF >0.0001'. The evidence for this variant shows MAF=0.00000797, below the threshold. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies when the variant is observed in healthy individuals (absence of recessive phenotype) scoring ≥4 points. The rule for BS2 is: 'Strong: applied in absence of Fanconi anemia phenotype, ≥4 points'. The evidence for this variant shows no healthy individual count or phenotype data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 applies when well-established functional studies show no damaging effect. The rule for BS3 is: 'Strong: functional studies show no damaging effect on protein or transcript'. The evidence for this variant shows no functional assays. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 applies when there is a lack of segregation in affected family members (LR≤0.05). The rule for BS4 is: 'Strong: lack of segregation evidence (LR≤0.05)'. The evidence for this variant shows no segregation analysis. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines, BP1_Strong applies to silent substitutions outside clinically important functional domains with no predicted splicing impact. The rule for BP1 is: 'Strong: silent substitution outside a (potentially) clinically important functional domain AND SpliceAI ≤0.1'. The evidence for this variant shows it is synonymous at codon 609, outside BRCA1 domains (aa 2–101, 1391–1424, 1650–1857), and SpliceAI predicts no effect. Therefore, this criterion is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when a variant is observed in trans with a pathogenic variant for a recessive disorder. The rule for BP2 is: 'Observed in trans with a pathogenic variant in a healthy individual or patient'. The evidence for this variant shows no such co-occurrence data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions without functional elements. The rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows it is a single nucleotide change, not an indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4 applies when multiple lines of computational evidence suggest no impact on gene or gene product. The rule for BP4 is: 'Supporting: multiple lines of computational evidence suggest no impact'. The evidence for this variant shows SpliceAI predicts no splicing impact, CADD score=0.19, and other in silico tools are benign. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, BP5 applies to variants co-occuring with pathogenic variants in different genes without specific phenotype. The rule for BP5 is: 'Supporting: combined LR against pathogenicity for co-observation'. The evidence for this variant shows no co-occurrence data. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, BP6 applies when a reputable source reports the variant as benign but evidence is unavailable. The rule for BP6 is: 'Supporting: reputable source reports variant as benign'. The evidence for this variant shows ClinVar entries from 4 labs and ENIGMA expert panel report it as Likely benign. Therefore, this criterion is applied at Supporting strength.
BP7 (Supporting)
According to standard ACMG guidelines, BP7 applies to synonymous variants with no predicted splicing impact. The rule for BP7 is: 'Supporting: synonymous variant with SpliceAI ≤0.1 and no splice consensus alteration'. The evidence for this variant shows SpliceAI predicts no effect on splicing. Therefore, this criterion is applied at Supporting strength.