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
OpenVariant summary: BRCA2 c.5851_5854delAGTT (p.Ser1951TrpfsX11) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251070 control chromosomes. c.5851_5854delAGTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Kwong_2012, Juwle_2012, Diez_2003, etc). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
The BRCA2 c.5851_5854del (p.Ser1951Trpfs*11) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in in individuals affected with breast and/or ovarian cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared), 32854451 (2020), 30702160 (2019), 29487695 (2018), 29470806 (2018), 29335924 (2018), 29084914 (2018), 26183948 (2015)) and renal cell carcinoma (PMID: 38496821 (2024)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
The c.5851_5854delAGTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5851 to 5854, causing a translational frameshift with a predicted alternate stop codon (p.S1951Wfs*11). This variant has been reported in multiple breast and/or ovarian cancer families across various ethnicities (Kwong A et al. Breast Cancer Res. Treat. 2009 Oct;117:683-6; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Vaidyanathan K et al. J. Biosci. 2009 Sep;34:415-22; Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Dodova RI et al. BMC Cancer. 2015 Jul;15:523; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333; Jakimovska M et al. Breast Cancer Res. Treat. 2018 Apr;168(3):745-753; Fanale D et al. Cancers (Basel), 2020 Aug;12:; Wessman S et al. Cancers (Basel), 2021 Oct;13:). Of note, this variant is also designated as 6079_6082delAGTT and 6079delAGTT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this variant is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this variant is interpreted as a disease-causing mutation.
"This variant has been reported in ClinVar as Pathogenic (19 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 S1951Wfs*11 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 | 95 bp |
| Donor Loss (DL) | 0.0 | 300 bp |
| Acceptor Gain (AG) | 0.0 | -121 bp |
| Donor Gain (DG) | 0.0 | 114 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
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 is a known mechanism of disease." The evidence for this variant shows: c.5851_5854del causes a frameshift leading to a premature stop (S1951Wfs*11) in BRCA2, a gene with well‐established loss‐of‐function mechanism, and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where LOF is an established disease mechanism.
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 results in the same amino acid change without impact on splicing." The evidence for this variant shows: c.5851_5854del is a frameshift, not a missense substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "Strong: De novo occurrence (with confirmed maternity and paternity) in a patient with the disease and no family history." The evidence for this variant shows: no information on de novo status. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong: 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: functional studies demonstrate that S1951Wfs*11 truncates critical domains of BRCA2, impairs nuclear localization, and disrupts homologous recombination. Therefore, this criterion is applied at Strong strength because well-established studies support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong: The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control studies with p≤0.05 and OR≥4)." The evidence for this variant shows: no case-control or prevalence data provided. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Moderate: Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: c.5851_5854del is a frameshift, not located in a defined hotspot or functional domain eligible for PM1. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent from controls in gnomAD v2.1 and v3.1 (non-cancer)." The evidence for this variant shows: it is not present in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Supporting: For BRCA2-related Fanconi anemia, co-occurrence with another variant in trans with appropriate phenotype." The evidence for this variant shows: no Fanconi anemia phenotype or co-occurring variant data. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Moderate: Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: it is a frameshift leading to truncation, which is covered under PVS1 rather than PM4. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Supporting/Moderate/Strong: Protein termination codon variant in an exon where a different proven pathogenic PTC variant has been seen before." The evidence for this variant shows: exon information is unavailable and we cannot confirm presence of other pathogenic PTCs in the same exon. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Moderate: Assumed de novo, without confirmation of paternity and/or maternity." The evidence for this variant shows: no de novo evidence provided. 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 in a gene definitively known to cause the disease." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense variant in a gene with low rate of benign missense variation and where pathogenic missense is common." The evidence for this variant shows: c.5851_5854del is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting: In silico evidence (BayesDel ≥0.30 or SpliceAI ≥0.2) for missense or splicing impact." The evidence for this variant shows: it is a frameshift and not evaluated by missense or splicing algorithms. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting: Patient phenotype is highly specific for a disease with a single genetic cause or limited genetic heterogeneity." The evidence for this variant shows: no phenotype or clinical data provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source recently reports variant as pathogenic but evidence not available for independent review." The evidence for this variant shows: ClinVar entries from 19 labs and ENIGMA expert panel classify it as pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Filter allele frequency >0.001 in gnomAD non-cancer populations." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: Filter allele frequency >0.0001 and ≤0.001 in gnomAD non-cancer populations." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong/Moderate/Supporting: Applied in absence of features of recessive disease (Fanconi anemia)." The evidence for this variant shows: no data on Fanconi anemia phenotype. Therefore, this criterion is not applied.
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: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong/Moderate/Supporting: Lack of segregation in affected family members." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 is: "Strong: Silent substitution, missense or in-frame indel outside functional domain with no splicing impact." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Supporting: Observed in trans with a pathogenic variant for a dominant disorder or in cis with another pathogenic variant." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In-frame deletion/insertions in a repetitive region without known function." The evidence for this variant shows: c.5851_5854del is a frameshift, not an in-frame event in a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense or in-frame variants with no predicted impact by BayesDel ≤0.18 and SpliceAI ≤0.1." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting: Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no co-occurring alternate pathogenic variant data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: Reputable source reports variant as benign but evidence unavailable." The evidence for this variant shows: no reputable benign reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: Silent or intronic variants outside conserved splice sites with no predicted splicing impact (SpliceAI ≤0.1)." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.