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
OpenThe p.Arg2520X variant in BRCA2 has been reported in >40 individuals with BRCA2-associated cancers (Hà kansson 1997, Bayraktar 2012, Castéra 2014, Schultheis 2014, Breast Cancer Information Core (BIC) database), and segregated with associated cancers in 2 affected relatives from 1 family. This variant has also been identified in 3/113554 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population This nonsense variant leads to a premature termination codon at position 2520, which is predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based on the low frequency in controls, presence in affected individuals, and predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting.
Variant summary: The BRCA2 c.7558C>T (p.Arg2520X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. If a protein product is made, it is predicted to truncate the helical domain, nucleic acid-binding/OB-fold domain, tower domain, and oligonucleotide/oligosaccharide-binding 1 domain (via InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.7721G>A/p.Trp2574X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/120748 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in many HBOC patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
PVS1, PM2, PP5
"This variant has been reported in ClinVar as Pathogenic (30 clinical laboratories) and as pathogenic (1 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The BRCA2 R2520* 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 studies have demonstrated that such truncating mutations impair the nuclear localization of BRCA2, which is essential for its normal function in maintaining the integrity of 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) | 0.07 | -39 bp |
| Donor Loss (DL) | 0.03 | 59 bp |
| Acceptor Gain (AG) | 0.0 | -483 bp |
| Donor Gain (DG) | 0.0 | -33 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule/finding 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 nonsense variant (R2520*) in BRCA2, a gene where LOF is a known mechanism, and it is not located in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant meets the definition of a null variant in a LOF gene.
PS1 (Not Applied)
According to VCEP guidelines, the rule/finding 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 nonsense variant, not a missense substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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: there is no information on de novo occurrence. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule/finding for PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: experimental studies demonstrate that truncating mutations at R2520* impair nuclear localization of BRCA2 and disrupt homologous recombination. Therefore, this criterion is applied at Strong strength because the functional studies are well-established and demonstrate a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule/finding for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control studies; p-value ≤0.05 and OR ≥4)." The evidence for this variant shows: no published case-control data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule/finding for PM1 is: "Moderate Apply PM1 for variants located in a (potentially) clinically important functional domain (BRCA2 PALB2 binding aa 10-40; DNA binding aa 2481-3186) that alter protein function." The evidence for this variant shows: it is a protein-truncating variant, not a missense or in-frame change. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule/finding for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25." The evidence for this variant shows: it is extremely rare in gnomAD (MAF = 0.00199%). Therefore, this criterion is applied at Supporting strength because the variant is absent or at extremely low frequency in controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule/finding for PM3 is: "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurring variants in the same gene." The evidence for this variant shows: no data on Fanconi Anemia phenotype or trans co-occurrence. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region may be pathogenic." The evidence for this variant shows: it is a nonsense variant resulting in truncation, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule/finding for PM5 is: "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before." The evidence for this variant shows: there is no specific data on other PTCs in the same exon for BRCA2. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule/finding for PP1 is: "Supporting Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP2 is: "Missense variant in gene with low rate of benign missense variants." The evidence for this variant shows: it is a nonsense variant, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule/finding for PP3 is: "Supporting Apply PP3 for missense or in-frame variants in a clinically important domain with predicted impact via protein change or splicing (BayesDel ≥0.30 or SpliceAI ≥0.2)." The evidence for this variant shows: it is a nonsense variant, not applicable. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule/finding for PP4 is: "Use only as part of multifactorial likelihood based on clinical data (breast cancer phenotype)." The evidence for this variant shows: no multifactorial clinical data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP5 is: "Reputable source recently reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence for this variant shows: although ClinVar reports pathogenic, VCEP/ACMG discourages use of PP5. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule/finding for BA1 is: "Stand Alone Filter allele frequency (FAF) is above 0.1% in gnomAD." The evidence for this variant shows: MAF = 0.00199% (<0.1%). Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule/finding for BS1 is: "Strong Filter allele frequency (FAF) is above 0.01% in gnomAD." The evidence for this variant shows: MAF = 0.00199% (<0.01%). Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule/finding for BS2 is: "Strong Applied in absence of features of recessive disease (Fanconi Anemia) with point-based system." The evidence for this variant shows: no phenotype data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule/finding for BS3 is: "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant shows: functional studies demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule/finding for BS4 is: "Strong Lack of segregation in affected family members." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule/finding for BP1 is: "Strong Apply BP1 for silent or missense variants outside a clinically important domain." The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant recessive gene." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to VCEP guidelines, the rule/finding for BP3 is: "Supporting In-frame indels in repetitive regions without known function." The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule/finding for BP4 is: "Supporting Missense or in-frame variants in a domain with no predicted impact via protein change or splicing." The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule/finding for BP5 is: "Use only for combined LR against pathogenicity based on multifactorial data; not applicable for co-observation with other genes." The evidence for this variant shows: no multifactorial data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP6 is: "Reputable source reports variant as benign but evidence is not available." The evidence for this variant shows: no such report. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule/finding for BP7 is: "Supporting Silent variants or intronic variants outside splice sites with no impact on splicing." The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied.