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OpenThis submission and the accompanying classification are no longer maintained by the submitter.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 (7 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 | -103 bp |
| Donor Loss (DL) | 0.0 | 145 bp |
| Acceptor Gain (AG) | 0.0 | 30 bp |
| Donor Gain (DG) | 0.0 | -415 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 (Y57=) change with no disruption of the coding sequence. 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..." The evidence for this variant shows no amino acid change (synonymous). Therefore, this criterion is not applied because the variant does not alter the protein sequence.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no de novo data available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect..." There are no functional studies for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to controls..." There are no case-control data showing enrichment in affected individuals. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 is: "Moderate Apply if variant is in a mutational hotspot or well-established functional domain without benign variation..." The variant is outside the defined BRCA2 functional domains (aa 10–40 and 2481–3186). 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 (non-cancer) and gnomAD v3.1 (non-cancer)." The evidence for this variant shows a MAF of 0.000796% in gnomAD (2/251 356 alleles), meeting the rarity threshold. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in population databases.
PM3 (Not Applied)
According to VCEP guidelines, PM3 is: "Apply for BRCA-related Fanconi Anemia cases with co-occurring variants..." There is no Fanconi Anemia or trans configuration evidence. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 is: "Protein length changes due to in-frame indels or stop-loss variants..." The variant is synonymous with no change in protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 is: "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen..." The variant is synonymous, not a PTC. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 is: "Assumed de novo, without confirmation of paternity and maternity..." There is no de novo evidence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, 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, PP2 is: "Missense variant in a gene with low rate of benign missense variation..." The variant is synonymous, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 is: "Supporting Apply PP3 for missense or in-frame variants inside a functional domain predicted damaging..." The variant is synonymous and computational tools predict no impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 is: "Use to capture combined LR based on multifactorial likelihood clinical data..." No phenotype-driven likelihood data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 is: "Reputable source reports variant as pathogenic..." Only benign assertions exist. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 is: "Stand Alone Filter allele frequency (FAF) > 0.1% in gnomAD..." The variant MAF (0.000796%) is well below 0.1%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 is: "Strong Filter allele frequency (FAF) > 0.01% and ≤0.1%..." The variant MAF (0.000796%) is below 0.01%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 is: "Applied in absence of features of recessive disease (Fanconi Anemia)..." No data on healthy individuals without FA phenotype. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 is: "Strong Well-established functional studies show no damaging effect..." No functional studies exist. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 is: "Strong Lack of segregation in affected family members..." No segregation data are available. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines, BP1_Strong is: "Apply BP1_Strong for silent substitution, missense or in-frame variants outside a functional domain AND no splicing predicted (SpliceAI ≤0.1)." The variant is a silent change at codon 57 (outside domains aa 10–40 and 2481–3186) with SpliceAI=0. Therefore, this criterion is applied at Strong strength because it meets domain and splicing criteria.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene..." No trans observations with pathogenic variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 is: "In-frame indels in repetitive regions without known function..." The variant is not an indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (e.g., conservation, splicing algorithms)." SpliceAI predicts no splicing impact (score=0) and CADD is benign. Therefore, this criterion is applied at Supporting strength because computational tools uniformly predict no effect.
BP5 (Not Applied)
According to VCEP guidelines, BP5 is: "Use to capture combined LR against pathogenicity based on multifactorial data..." No multifactorial data or co-observation scenarios. 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 for independent evaluation." ClinVar and ENIGMA report this variant as Likely Benign. Therefore, this criterion is applied at Supporting strength because multiple reputable sources assert benign status without underlying data.
BP7 (Supporting)
According to standard ACMG guidelines, BP7 is: "Synonymous variant for which splicing prediction algorithms predict no impact on splicing and the nucleotide is not highly conserved." SpliceAI predicts no splicing impact (score=0). Therefore, this criterion is applied at Supporting strength because it is a synonymous change with no predicted splicing effect.