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
OpenThis submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
"This variant has been reported in ClinVar as Likely benign (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) | 0.01 | -1 bp |
| Donor Loss (DL) | 0.0 | -187 bp |
| Acceptor Gain (AG) | 0.01 | 22 bp |
| Donor Gain (DG) | 0.01 | 71 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies to null variants at canonical ±1,2 splice positions in BRCA2. The evidence for this variant shows it is at position c.426-22, outside the ±1,2 splice site. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies when a variant has the same amino acid change as a known pathogenic variant. This is an intronic variant with no predicted protein change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 applies to confirmed de novo occurrences. 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 showing a damaging effect. No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 requires a statistically significant increase in variant prevalence in affected individuals. No case-control or cohort data exist for this variant. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to variants within critical functional domains. This variant is intronic outside of protein domains. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, PM2_Supporting requires absence from controls in gnomAD. The evidence for this variant shows a MAF of 0.00249% in gnomAD. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP guidelines, PM3 applies to variants in trans with a pathogenic variant in confirmed Fanconi Anemia cases. No FA 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 such as in-frame indels. This variant is intronic. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues with known pathogenic missense mutations. This variant is intronic. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo without confirmation. No de novo information is available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 requires co-segregation with disease in multiple family members. 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 rates of benign missense variation. This variant is intronic. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 requires computational evidence supporting a deleterious effect. In silico splicing predictors (SpliceAI 0.01) and CADD (-0.43) predict no impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 applies when patient phenotype matches gene-specific disease with high specificity. No phenotypic data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies to assertions of pathogenicity by reputable sources. The variant is reported as likely benign. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 requires a filter allele frequency >0.1% in gnomAD. The variant MAF is 0.00249%, below threshold. Therefore, this criterion is not applied.
BS1 (Supporting)
According to VCEP guidelines, BS1_Supporting is: "Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001)". The evidence for this variant shows a MAF of 0.00249% in gnomAD. Therefore, this criterion is applied at Supporting strength because the allele frequency falls within the specified range.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies in the absence of a Fanconi Anemia phenotype in multiple individuals. No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires well‐established functional studies showing no damaging effect. No functional studies have been performed. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 requires lack of segregation in affected family members. No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, BP1 applies to silent or missense variants outside functional domains with no splice impact. This is an intronic variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies to observations in trans with a pathogenic variant in autosomal dominant disorders. No such observations exist. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame deletions/insertions in repetitive regions. This variant is intronic with no indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, BP4 is: "Intronic variants outside of the native donor and acceptor splice sites (i.e. not ±1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1)". The evidence for this variant shows it is at position –22 from the exon and SpliceAI predicts no impact (0.01). Therefore, this criterion is applied at Supporting strength because it meets the specified splicing criteria.
BP5 (Not Applied)
According to VCEP guidelines, BP5 applies when a variant is observed in a case with an alternate molecular basis for disease. No such co-occurrence data are available. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows ClinVar assertions of Likely Benign by two clinical laboratories without full data. Therefore, this criterion is applied at Supporting strength.
BP7 (Supporting)
According to VCEP guidelines, BP7_Supporting is: "Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met". The evidence for this variant shows it is at position –22 and BP4 is met. Therefore, this criterion is applied at Supporting strength because it lies beyond the conserved splice motif and computational evidence supports no impact.