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
Open"This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (1 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 | 146 bp |
| Donor Loss (DL) | 0.0 | -93 bp |
| Acceptor Gain (AG) | 0.0 | -111 bp |
| Donor Gain (DG) | 0.0 | 145 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 synonymous change (S353=) with no predicted impact on splicing. Therefore, this criterion is not applied because the variant is not a null variant.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing)." The evidence for this variant shows: it is a synonymous change with no amino acid alteration. Therefore, this criterion is not applied because there is no protein change.
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." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied due to missing parental testing data.
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 on the gene or gene product." The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied because functional data are missing.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls (OR ≥4, p ≤0.05)." The evidence for this variant shows: no case‐control or affected individual data are available. Therefore, this criterion is not applied due to missing case-control data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or functional domain without benign variation." The evidence for this variant shows: it is a synonymous change at amino acid 353, outside of defined functional domains. Therefore, this criterion is not applied because it is not in a critical domain.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer) and gnomAD v3.1 (non-cancer)." The evidence for this variant shows: it is present in gnomAD with MAF 0.00121%. Therefore, this criterion is not applied because the variant is not absent from controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3_Supporting is: "Apply for patient with Fanconi Anemia phenotype and co-occurring variants in BRCA2." The evidence for this variant shows: no Fanconi Anemia phenotype or co‐occurrence data. Therefore, this criterion is not applied due to missing phenotype and co-occurrence data.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: it is synonymous with no protein length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change has been established as pathogenic." The evidence for this variant shows: it is synonymous, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members (LR ≥2.08:1)." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied due to missing segregation data.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene where missense is a common mechanism of disease and where there is a low rate of benign missense variation." The evidence for this variant shows: it is synonymous and not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Apply PP3 for variants with BayesDel no-AF score ≥0.30 inside functional domains or SpliceAI ≥0.2." The evidence for this variant shows: SpliceAI score = 0 and BayesDel score not above threshold. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting Phenotype specificity based on multifactorial likelihood data (LR ≥2.08:1)." The evidence for this variant shows: no clinical phenotype or multifactorial data. Therefore, this criterion is not applied due to missing phenotype data.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source classifies variant as pathogenic but evidence not available for independent evaluation." The evidence for this variant shows: no reputable source classifies it as pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone FAF >0.1% in gnomAD non-cancer populations." The evidence for this variant shows: MAF = 0.00121% (<0.1%). Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Filter Allele Frequency (FAF) >0.01% in gnomAD non-cancer populations." The evidence for this variant shows: MAF = 0.00121% (<0.01%). Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Applied in absence of Fanconi Anemia phenotype (≥4 unaffected individuals)." The evidence for this variant shows: no phenotype data available. Therefore, this criterion is not applied due to missing clinical phenotype information.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established functional studies show no damaging effect on protein function." The evidence for this variant shows: no functional assays performed. Therefore, this criterion is not applied because functional data are missing.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected members (LR ≤0.05:1)." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied due to missing segregation data.
BP1 (Strong)
According to VCEP guidelines, the rule for BP1 is: "Strong Apply BP1 for silent substitution, missense or in-frame variants outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)." The evidence for this variant shows: it is a silent change at aa353 (outside defined domains) with SpliceAI = 0. Therefore, this criterion is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant in the same gene for a recessive disorder." The evidence for this variant shows: no trans observation data. Therefore, this criterion 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 a known function." The evidence for this variant shows: it is synonymous, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting for variants inside functional domains with no predicted impact via protein or splicing." The evidence for this variant shows: it is a silent change outside domains; computational tools predict no splicing impact. Therefore, this criterion is not applied because it does not meet the domain requirement.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Use only to capture combined LR against pathogenicity based on multifactorial data; not for co-observation." The evidence for this variant shows: no multifactorial data. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence is not available for independent evaluation." The evidence for this variant shows: multiple laboratories in ClinVar and the ENIGMA panel classify it as Benign/Likely Benign. Therefore, this criterion is applied at Supporting strength.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting Silent variant inside a functional domain if BP4 met, or intronic variants outside splice motifs if BP4 met." The evidence for this variant shows: it is silent outside domains and BP4 is not met. Therefore, this criterion is not applied.