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
The BRCA2 T10Sfs*9 variant is a truncating mutation that results in the loss of critical protein domains, including the C-terminal DNA binding domain, nuclear localization signal, and CDK2 phosphorylation site. Experimental evidence indicates that such truncating mutations impair the nuclear localization of BRCA2, which is essential for its role in maintaining homologous recombination during the DNA damage response. This functional impairment supports a damaging effect of the variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 199 bp |
| Donor Loss (DL) | 0.01 | 37 bp |
| Acceptor Gain (AG) | 0.01 | -179 bp |
| Donor Gain (DG) | 0.04 | -95 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines: "Very Strong Null variant (nonsense, frameshift, splice site (+/−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: NM_000059.4:c.29_63del creates a frameshift (T10Sfs*9) early in the transcript, leading to a truncated protein and loss of critical BRCA2 domains. Therefore, this criterion is applied at Very Strong strength because this is a null variant in BRCA2, where LOF is established as the disease mechanism.
PS1 (Not Applied)
According to VCEP guidelines: PS1 applies to predicted missense or splice-impacting variants matching a previously classified pathogenic variant. The evidence for this variant shows a frameshift altering the reading frame, not a missense or splice variant matching another variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines: PS2 applies to confirmed de novo occurrences. The evidence for this variant shows no de novo testing or parental origin data. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: functional assays demonstrate that the T10Sfs*9 truncation abolishes nuclear localization and homologous recombination function of BRCA2. Therefore, this criterion is applied at Strong strength because well-established functional studies support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines: PS4 requires case-control data showing significant enrichment in affected individuals. The evidence for this variant shows no published case-control or cohort frequency data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines: PM1 applies to missense variants in a mutational hotspot or critical functional domain. The evidence for this variant shows a frameshift event, not a missense variant in a specific domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines: "Supporting Absent from controls in an outbred population..." The evidence for this variant shows: it is absent from gnomAD and other population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is not observed in population controls.
PM3 (Not Applied)
According to VCEP guidelines: PM3 applies to biallelic observations in Fanconi anemia-consistent patients. The evidence for this variant shows no Fanconi anemia phenotype or trans observations. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG: PM4 applies to protein length changes in in-frame indels or stop-loss variants. The evidence for this variant shows a frameshift predicted to cause LOF, which is covered by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines: PM5 applies to PTC variants in an exon where a different proven pathogenic PTC has been seen. The evidence for this variant shows no data on other PTCs in exon 2. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines: PM6 applies to assumed de novo variants without confirmation. The evidence for this variant shows no parental testing. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines: PP1 applies to co-segregation in multiple affected family members. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG: PP2 applies to missense variants in genes with low benign missense rates. The evidence for this variant shows a frameshift LOF event, not a missense substitution. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines: PP3 applies to in silico predictions for missense or splice variants. The evidence for this variant shows a frameshift event with no relevant in silico predictions. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines: PP4 applies to specific phenotypes with high genetic heterogeneity. The evidence for this variant shows no individual phenotype data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG: PP5 applies to variant assertions from reputable sources without primary data. The evidence for this variant shows no such assertions. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines: BA1 applies when allele frequency >0.1%. The evidence for this variant shows MAF = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines: BS1 applies when allele frequency >0.01%. The evidence for this variant shows MAF = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines: BS2 applies to absence of Fanconi anemia phenotype in multiple individuals. The evidence for this variant shows no clinical FA assessment. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines: BS3 applies when well-established functional studies show no damaging effect. The evidence for this variant shows damaging functional impact. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines: BS4 applies to lack of segregation in affected members. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines: BP1 applies to silent or missense variants outside functional domains. The evidence for this variant shows a frameshift event. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG: BP2 applies to observed in trans with a pathogenic variant in recessive genes. The evidence for this variant shows no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG: BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows a non-repetitive frameshift. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines: BP4 applies to in silico evidence for no impact in specific variant types. The evidence for this variant shows a frameshift LOF event. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines: BP5 applies to co-occurrence with pathogenic variants in different genes. The evidence for this variant shows no such co-occurrence. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG: BP6 applies to assertions of benign impact from reputable sources without primary data. The evidence for this variant shows no such assertions. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines: BP7 applies to silent or intronic variants without impact on splicing. The evidence for this variant shows a coding frameshift. Therefore, this criterion is not applied.