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.10222A>T (p.Lys3408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein but not expected to undergo nonsense mediated decay. The variant allele was found at a frequency of 1.7e-05 in 1613940 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (1.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.10222A>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome without strong evidence for or against pathogenicity (example: Pirim_2020, Darst_2021, Bisgin_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32599251, 32853339, 35753294). ClinVar contains an entry for this variant (Variation ID: 51056). Based on the evidence outlined above, the variant was classified as likely benign.
"This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (6 clinical laboratories) and as Benign (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The BRCA2 K3408* variant is a truncating mutation that results in the loss of critical protein domains, including the C-terminal DNA binding domain, the nuclear localization signal, and the CDK2 phosphorylation site. Experimental studies indicate 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) | 0.02 | -149 bp |
| Donor Loss (DL) | 0.0 | 212 bp |
| Acceptor Gain (AG) | 0.0 | -485 bp |
| Donor Gain (DG) | 0.0 | -12 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines: "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 a nonsense change (K3408*) predicted to result in loss of critical C-terminal domains and subject to NMD. Therefore, this criterion is applied at Very Strong strength because it is a null variant in BRCA2, a gene with established LOF mechanism.
PS1 (Not Applied)
According to VCEP guidelines: "Strong Apply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change..." The evidence for this variant shows a novel nonsense change, not a missense with identical amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." No de novo parental data are available for this variant. 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 experimental data demonstrating that truncation at K3408 impairs nuclear localization and homologous recombination function. Therefore, this criterion is applied at Strong strength because functional studies support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines: "Strong The prevalence of the variant in affected individuals is significantly increased compared to controls (p≤0.05 and OR≥4)." No case-control data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines: "Located in a mutational hot spot or well-established functional domain without benign variation." This nonsense variant affects the C-terminus but is classified under PVS1. No hotspot or distinct domain criterion is needed. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines: "Supporting Absent from controls in an outbred population from gnomAD v2.1 and v3.1." The evidence shows a MAF of 0.000708% in gnomAD, below thresholds. Therefore, this criterion is applied at Supporting strength because the variant is absent/rare in population databases.
PM3 (Not Applied)
According to VCEP guidelines: "Supporting Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrence of variants in trans." No FANCONI phenotype or trans variant data exist. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines: "Protein length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants." This is a nonsense variant covered by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before." This is a nonsense variant and no PTC at this codon is documented. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines: "Assumed de novo, without confirmation of paternity and maternity." No de novo data are provided. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines: "Supporting Co-segregation with disease in multiple affected family members..." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines: "Missense variant in a gene with low rate of benign missense variation..." This is a nonsense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines: "Supporting computational evidence (BayesDel, SpliceAI...)." The in silico scores (CADD 4.41, SpliceAI 0.02) do not predict deleterious effect. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines: "Supporting phenotype specificity and multifactorial likelihood for breast cancer." No detailed phenotype or likelihood data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines: "Reputable source reports variant as pathogenic without available evidence." ClinVar interpretations are conflicting; no single reputable assertion. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines: "Stand Alone allele frequency >0.1% in gnomAD." The variant frequency is 0.000708%, below the cutoff. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines: "Strong Filter allele frequency >0.01%." The allele frequency is below this threshold. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines: "Strong Applied in absence of Fanconi Anemia phenotype." No phenotype data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines: "Strong Well-established functional studies show no damaging effect." Functional studies show damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines: "Strong Lack of segregation in affected members." No segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines: "Strong silent or missense outside functional domain with no splice impact." This is a nonsense variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines: "Observed in trans with a pathogenic variant for a recessive disorder or observed in cis..." No such co-observation data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines: "In-frame indels in repetitive region without known function." Not applicable. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines: "Supporting no predicted impact via protein or splicing." Computational tools do not predict damaging for in-frame/missense; nonsense is covered by PVS1. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines: "Supporting observation with alternate pathogenic variant in different gene." No such co-occurrence. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines: "Reputable source reports variant as benign without evidence." No such source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines: "Supporting silent variant or intronic with no splicing impact." This is a nonsense variant. Therefore, this criterion is not applied.