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
OpenThis sequence change falls in intron 2 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 433683). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
"This variant has been reported in ClinVar as Uncertain significance (2 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) | 0.88 | 103 bp |
| Donor Loss (DL) | 0.93 | 5 bp |
| Acceptor Gain (AG) | 0.0 | -13 bp |
| Donor Gain (DG) | 0.0 | -97 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies to null variants including splice site (donor/acceptor +/−1,2). The variant NM_007294.4:c.80+5G>C is at position +5, outside the canonical splice donor site positions ±1/2. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies when an exonic or intronic variant has the same predicted impact on splicing as a previously classified pathogenic variant. There is no known pathogenic BRCA1 variant with identical splicing impact at this position. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 applies to de novo variants with confirmed maternity and paternity. No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP and standard ACMG guidelines, PS3 requires well-established functional studies supportive of a damaging effect. No such functional data exist for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 applies when case–control data show a significant increase in variant prevalence in affected individuals. No case–control or prevalence data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to variants within clinically important functional domains. NM_007294.4:c.80+5G>C is intronic and does not alter a protein domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2_Supporting is “Absent from controls in an outbred population, from gnomAD v2.1 and v3.1.” The variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, PM3 applies for biallelic variants in Fanconi Anemia cohorts with appropriate phenotypes. No such data are available for this variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to protein length changes. This intronic variant does not alter protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 applies to protein termination codon variants in exons with previously seen pathogenic PTCs. This variant is intronic. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to unconfirmed de novo variants. No de novo information is available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 applies for co-segregation with disease in families. No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense rate. This variant is intronic. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, PP3_Supporting is “Apply PP3 for predicted splicing (SpliceAI ≥0.2) for intronic variants outside of donor and acceptor 1,2 sites.” SpliceAI predicts donor loss at +5 with score 0.93. Therefore, PP3 is applied at Supporting strength.
PP4 (Not Applied)
According to VCEP guidelines, PP4 applies to combined multifactorial clinical evidence. No such clinical likelihood data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies to assertions by reputable sources without primary evidence. No such assertion exists beyond VUS reports. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies when allele frequency >0.1% in gnomAD. The variant is absent. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies when allele frequency >0.01% in gnomAD. The variant is absent. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies to healthy individuals without Fanconi Anemia phenotype. No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires functional studies showing no damaging effect. No such data exist. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 applies for lack of segregation in families. No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, BP1_Strong applies to silent or missense variants outside functional domains with no splicing predicted. This is intronic with predicted splicing impact. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies to observation in trans with a pathogenic variant for a dominant disorder. No such co-occurrence data are available. 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 impact. Not applicable to this SNV. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 applies when SpliceAI ≤0.1 and no protein impact predicted. SpliceAI is 0.93, indicating splicing impact. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, BP5 applies to combined clinical evidence against pathogenicity. No such multifactorial data exist. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies to likely benign assertions without primary data. No such assertion exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 applies to intronic variants beyond +7 or silent variants with no splicing impact. This variant is at +5 with predicted splicing impact. Therefore, this criterion is not applied.