BRCA2 c.10222A>T, p.Lys3408Ter
NM_000059.4:c.10222A>T
Pathogenic
The K3408* variant introduces a premature stop codon in BRCA2, resulting in loss of essential C-terminal domains. It meets PVS1_VeryStrong (null variant LOF mechanism), PS3_Strong (functional studies show damaging effect), and PM2_Supporting (absent/rare in controls), which collectively justify a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
Genetic Information
Gene & Transcript Details
Gene
BRCA2
Transcript
NM_000059.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000013.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000059.2 | Alternative | 27 exons | Forward |
| NM_000059.3 | RefSeq Select | 27 exons | Forward |
Variant Details
HGVS Notation
NM_000059.4:c.10222A>T
Protein Change
K3408*
Location
Exon 27
(Exon 27 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.10222A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000708%
Very Rare
Highest in Population
European (non-Finnish)
0.00155%
Rare
Global: 0.000708%
European (non-Finnish): 0.00155%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282408Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000708%, 2/282408 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00155%, 2/128950 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Uncertain Significance (VUS)
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
2 VUS
6 LB
2 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
Variant 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.
Clinical Statement
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).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
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.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 4.41
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
PP2 (Not Applied) Strength Modified
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Filter allele frequency >0.01%." The allele frequency is below this threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Applied in absence of Fanconi Anemia phenotype." No phenotype data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Lack of segregation in affected members." No segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "In-frame indels in repetitive region without known function." Not applicable. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting observation with alternate pathogenic variant in different gene." No such co-occurrence. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Reputable source reports variant as benign without evidence." No such source. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting silent variant or intronic with no splicing impact." This is a nonsense variant. Therefore, this criterion is not applied.