BRCA2 c.5899A>T, p.Lys1967Ter
NM_000059.4:c.5899A>T
Pathogenic
c.5899A>T (K1967*) in BRCA2 is a predicted loss-of-function nonsense variant absent from controls, with strong functional evidence of damaging effect and supporting ClinVar assertions. It meets PVS1 (Very Strong) and PS3 (Strong) plus supporting PM2 and PP5, consistent with Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
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.5899A>T
Protein Change
K1967*
Location
Exon 11
(Exon 11 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.5899A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change creates a premature translational stop signal (p.Lys1967*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (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 K1967* variant is a truncating mutation that likely results in loss of function. Functional studies indicate that truncating mutations in BRCA2 impair nuclear localization, which is essential for its role in maintaining homologous recombination during DNA damage response. This loss of function is associated with an increased risk of developing various cancers, including breast, ovarian, prostate, and pancreatic cancers.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 5.00
Neutral: Show all
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 it is a nonsense change (K1967*) predicted to truncate the protein. Therefore, this criterion is applied at Very Strong strength because BRCA2 LOF is a known mechanism and this is a null variant not in the last exon.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Apply PS1 for predicted missense substitutions..." The evidence for this variant shows it is a nonsense change, not a missense substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: PS2 requires de novo occurrence with confirmed maternity and paternity. No parental testing 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 functional studies indicate that truncating BRCA2 variants impair nuclear localization and homologous recombination. Therefore, this criterion is applied at Strong strength because well-established assays demonstrate damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: "The prevalence of the variant in affected individuals is significantly increased compared to controls... p-value ≤0.05 and OR ≥4." No case-control or cohort data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM1 applies to variants in mutational hot spots or functional domains without benign variation. There is no evidence that K1967 lies within a defined critical functional domain. 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 for this variant shows it is not observed in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: PM3 applies to biallelic variants in Fanconi Anemia patients with phenotype. There is no evidence this variant is part of a biallelic genotype in FA. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM4 applies to protein length changes due to in-frame indels or stop-loss variants. This is a nonsense variant handled by PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM5 applies to novel missense changes at amino acid residues where other pathogenic missense changes occur. This is a PTC variant and PVS1 covers null variants. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM6 applies to assumed de novo cases without confirmation. No de novo or parental data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: PP1 requires segregation data 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: PP2 applies to missense variants in genes with low benign missense rate. Variant is nonsense, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: PP3 applies to missense or splice predictions with BayesDel ≥0.30 or SpliceAI ≥0.2. This is a nonsense variant and SpliceAI score is 0. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines: PP4 applies to phenotype specificity in breast/ovarian cancer families with multifactorial likelihood data. No detailed phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: "PP5: Reputable source reports variant as pathogenic, but evidence not available." The evidence for this variant shows ClinVar entries from two clinical labs reporting Pathogenic. Therefore, this criterion is applied at Supporting strength because of reputable assertions without accessible primary data.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: BA1 requires allele frequency >0.1% in control populations. The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: BS1 requires allele frequency >0.01%. The variant is not observed in population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: BS2 applies to observations in unaffected individuals for recessive traits. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: BS3 requires well-established functional studies showing no damaging effect. Available functional data show damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: BS4 requires lack of segregation in affected family members. No segregation data exist. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines: BP1 applies to silent or missense/in-frame variants outside key domains. Variant is nonsense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP2 applies when variant is observed in trans with a pathogenic variant for a dominant disorder. No such observations reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP3 applies to in-frame indels in repetitive regions. This is a nonsense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: BP4 applies to in silico benign predictions for missense/in-frame/splice variants. This is a nonsense variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: BP5 applies to co-occurrence with pathogenic variants in other genes without specific phenotype. No co-occurrence data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP6 applies when a reputable source reports benign without available evidence. No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: BP7 applies to silent or intronic variants with no splice impact. This is a nonsense variant. Therefore, this criterion is not applied.