BRCA2 c.5644_5647del, p.Ser1882LysfsTer26
NM_000059.4:c.5644_5647del
Pathogenic
The frameshift variant meets PVS1 (Very Strong LOF) and PS3 (Strong functional evidence) along with supportive PM2 and PP5, fulfilling criteria for Pathogenic classification.
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.5644_5647del
Protein Change
S1882Kfs*26
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1882: S1882P
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.5644_5647del
Active Tracks
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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
2 publications
Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The c.5644_5647delTCAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5644 to 5647, causing a translational frameshift with a predicted alternate stop codon (p.S1882Kfs*26). This variant has been reported in breast cancer patients from several cohorts (Brianese RC et al. Breast Cancer Res Treat, 2018 Feb;167:803-814; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Palmero EI et al. Sci Rep, 2018 Jun;8:9188; Ajaz S et al. Front Genet, 2022 Mar;13:820610). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.Ser1882Lysfs*26) 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 cancer (PMID: 29907814). ClinVar contains an entry for this variant (Variation ID: 254561). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
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.
Expert Panel Reviews
Pathogenic
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
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
ClinVar reports other pathogenic variants at position 1882: S1882P
PM5 criterion applied.
Functional Summary
The BRCA2 S1882Kfs*26 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 studies have demonstrated that such truncating mutations impair the nuclear localization of BRCA2, which is essential for its 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
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
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 LOF is a known mechanism of disease." The evidence for this variant shows: NM_000059.4:c.5644_5647del causes a frameshift (S1882Kfs*26), not in the last exon, resulting in LOF. Therefore, this criterion is applied at Very Strong strength because it is a null variant in BRCA2, a gene with LOF disease mechanism, per VCEP PVS1 flowchart.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PS1 is: "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: it is a frameshift, not a missense substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo or parental testing data available. Therefore, this criterion is not applied.
PS3
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 the frameshift mutation impairs nuclear localization and homologous recombination function. Therefore, this criterion is applied at Strong strength.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared to controls (case-control data)." The evidence for this variant shows: no case-control or OR data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PM1 is: "Located in a mutational hot spot and/or critical functional domain without benign variation." The evidence for this variant shows: it is a frameshift, not a variant within a defined critical domain for missense. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: the rule for PM2 is: "Supporting Absent from controls in gnomAD v2.1 and v3.1." The evidence for this variant shows: MAF=0% in gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive phenotype." The evidence for this variant shows: no data on trans configuration or Fanconi anemia phenotype. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a frameshift resulting in truncation, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM5 is: "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 location is unknown, so cannot confirm other PTC variants in the same exon. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo or parental testing data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PP3 is: "Predicted deleterious effect by multiple computational methods." The evidence for this variant shows: frameshift variants are not subject to missense/in-frame computational predictions, and SpliceAI shows no splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype or family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: the rule for PP5 is: "Reputable source reports as pathogenic but evidence not available for independent evaluation." The evidence for this variant shows: ClinVar (3 labs) and ENIGMA expert panel report it as Pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BA1 is: "Allele frequency >0.1% in gnomAD." The evidence for this variant shows: allele frequency = 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS1 is: "Allele frequency >0.01% and ≤0.1% in gnomAD." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS2 is: "Observed in healthy adult individuals, no features of recessive disease." The evidence for this variant shows: no healthy adult evaluation or Fanconi anemia assessment data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS3 is: "Well-established functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS4 is: "Lack of segregation in affected members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BP1 is: "Missense variant outside functional domain with no splicing impact." The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for BP2 is: "Observed in trans with pathogenic variant for dominant disorder or in cis with pathogenic variant." The evidence for this variant shows: no such co-occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for BP3 is: "In-frame indel in repetitive region without known function." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BP4 is: "No predicted impact on protein or splicing by computational evidence." The evidence for this variant shows: computational tools not applicable to frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no co-existing pathogenic variant in different gene reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for BP6 is: "Reputable source reports as benign but evidence not available." The evidence for this variant shows: reported as pathogenic, not benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for BP7 is: "Silent variant with no splicing impact." The evidence for this variant shows: it is not silent. Therefore, this criterion is not applied.