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 c.2775delT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 2775, causing a translational frameshift with a predicted alternate stop codon (p.T926Pfs*34). This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat. 2018 Jul;170:189-196). 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 alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
This sequence change creates a premature translational stop signal (p.Thr926Profs*34) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 418078). For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (3 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 T926Pfs*34 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.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -63 bp |
| Donor Loss (DL) | 0.0 | 26 bp |
| Acceptor Gain (AG) | 0.0 | -445 bp |
| Donor Gain (DG) | 0.01 | -376 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 (LOF) is a known mechanism of disease." The evidence for this variant shows: c.2775del is a frameshift truncating variant leading to a premature stop codon in BRCA2, not in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in a gene with LOF 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 is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI ≤0.1))." The evidence for this variant shows: it is a frameshift variant, not a missense substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
No specific VCEP or standard ACMG rule text was provided for PS2 in the VCEP guidelines. Parental testing data are not available to confirm de novo occurrence. 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." The evidence for this variant shows: functional studies demonstrate that the T926Pfs*34 truncation disrupts critical domains and impairs nuclear localization, supporting a damaging effect. Therefore, this criterion is applied at Strong strength because well-established functional data confirm damage.
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 (p ≤0.05 and OR ≥4)." The evidence for this variant shows: no case-control data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
No specific VCEP or standard ACMG rule text was provided for PM1 in the VCEP guidelines. There is no evidence that the variant lies within a mutational hot spot or critical domain beyond LOF. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 and v3.1 non-cancer subset." The evidence for this variant shows: not found in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA) and co-occurrence of variants." The evidence for this variant shows: no FA phenotype or co-occurrence data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
No specific VCEP or standard ACMG rule text was provided for PM4 in the VCEP guidelines. The variant is a frameshift LOF, not an in-frame alteration. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule 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: no specific data about other PTCs in the same exon. Therefore, this criterion is not applied.
PM6 (Not Applied)
No specific VCEP or standard ACMG rule text was provided for PM6 in the VCEP guidelines. De novo occurrence assumed without confirmation is not supported by data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members measured quantitatively." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
No specific VCEP or standard ACMG rule text was provided for PP2 in the VCEP guidelines. Therefore, this criterion is not applied due to lack of evidence of missense constraint.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting: Missense or in-frame variants inside a domain predicted deleterious by BayesDel or SpliceAI ≥0.2." The evidence for this variant shows: it is a frameshift variant, not a missense or splice-predicted variant. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Specific phenotype with high genetic heterogeneity captured by multifactorial likelihood data." The evidence for this variant shows: no phenotype or multifactorial data. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar and ENIGMA expert panel report pathogenic. Therefore, this criterion is applied at Supporting strength because reputable sources report pathogenicity without independent evidence.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Filter allele frequency >0.1% in gnomAD non-cancer subset." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: Filter allele frequency >0.01% and ≤0.1% in gnomAD." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Absence of Fanconi Anemia features in carriers." The evidence for this variant shows: no data on FA 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." The evidence for this variant shows: functional studies demonstrate damage. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected family members measured quantitatively." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 is: "Silent or missense variants outside critical domains with no splicing effect." The evidence for this variant shows: it is a frameshift truncation. Therefore, this criterion is not applied.
BP2 (Not Applied)
No specific VCEP or standard ACMG rule text was provided for BP2 in the VCEP guidelines. Therefore, this criterion is not applied.
BP3 (Not Applied)
No specific VCEP or standard ACMG rule text was provided for BP3 in the VCEP guidelines. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense/in-frame variants inside a domain with no predicted impact (BayesDel no-AF ≤0.18 and SpliceAI ≤0.1)." The evidence for this variant shows: it is a frameshift variant. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Cases with pathogenic variants in multiple genes and no specific phenotype." The evidence for this variant shows: no co-occurrence with other gene variants. Therefore, this criterion is not applied.
BP6 (Not Applied)
No specific VCEP or standard ACMG rule text was provided for BP6 in the VCEP guidelines. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Silent or intronic variants with no impact on splicing confirmed by no damaging functional data." The evidence for this variant shows: it is a frameshift variant. Therefore, this criterion is not applied.