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""
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 | 50 bp |
| Donor Loss (DL) | 0.0 | 308 bp |
| Acceptor Gain (AG) | 0.0 | -180 bp |
| Donor Gain (DG) | 0.0 | -275 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies to null variants in a gene where loss of function is a known mechanism. The evidence for NM_000059.4:c.2090A>C shows it is a missense variant, not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies when a variant causes the same amino acid change as a previously established pathogenic variant. There is no report of a K697T change previously classified as pathogenic. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence with parental testing. No parental data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 requires well-established functional studies showing a damaging effect. No functional assays have been performed for K697T. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 requires case-control data showing significant enrichment in affected individuals. No such data exist for this variant. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to variants in clinically important functional domains (BRCA2 aa 10–40 or 2481–3186). K697T lies outside these domains. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2_Supporting: "Absent from controls in an outbred population, from gnomAD v2.1 and v3.1." The evidence shows this variant is not found in gnomAD. Therefore, PM2 is applied at Supporting strength because the variant is absent from control populations per VCEP PM2 criteria.
PM3 (Not Applied)
According to VCEP guidelines, PM3 requires evidence of co-occurrence in trans with a pathogenic variant in a Fanconi anemia phenotype. No such data are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels). This is a missense variant with no length change. Therefore, PM4 is not applied.
PM5 (Moderate)
According to standard ACMG guidelines, PM5_Moderate: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." The evidence shows a pathogenic missense at K697 has been reported. Therefore, PM5 is applied at Moderate strength because K697 is a residue with a known pathogenic missense change.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without parental confirmation. No de novo assumption is documented. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 requires co-segregation evidence in multiple affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation and where missense is a common mechanism. BRCA2 has many benign missense variants and no specific PP2 guidance. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 applies when computational evidence predicts a deleterious effect inside a functional domain or predicted splicing impact (SpliceAI ≥0.2). In silico tools predict no impact and SpliceAI = 0. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 requires phenotype specificity and multifactorial likelihood data. No clinical phenotype data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 requires a reputable source classification of the variant as pathogenic. This variant is not in ClinVar or equivalent. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies to variants with allele frequency >0.1% in gnomAD. This variant is absent. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies to variants with filter allele frequency >0.01% in gnomAD. This variant is absent. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 requires observation in healthy adults. No such observations are reported. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires well-established functional studies showing no damaging effect. No functional data exist. Therefore, BS3 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, BS4 is not applied.
BP1 (Strong)
According to VCEP guidelines, BP1_Strong: "Missense variants outside clinically important functional domains AND no splicing predicted (SpliceAI ≤0.1)." K697T lies outside BRCA2 domains and SpliceAI = 0. Therefore, BP1 is applied at Strong strength because it is a missense change outside defined functional domains with no predicted splicing impact.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 requires co-occurrence in cis with a pathogenic variant. No co-occurrence data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense variant. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 applies to variants inside functional domains with no predicted impact. K697T is outside domains. Therefore, BP4 is not applied under VCEP specifications.
BP5 (Not Applied)
According to VCEP guidelines, BP5 requires multifactorial clinical data on co-observation with other pathogenic variants. No such data exist. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 requires a reputable source classification of the variant as benign. This variant is not in such sources. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 applies to silent or intronic variants outside splice sites with no impact. This is a missense variant. Therefore, BP7 is not applied.