BRCA2 c.5722_5723del, p.Leu1908ArgfsTer2
NM_000059.4:c.5722_5723del
COSMIC ID: COSM7212222
Pathogenic
The c.5722_5723delCT (L1908Rfs*2) frameshift variant introduces a premature stop codon in BRCA2, satisfying PVS1 (Very Strong) and PS3 (Strong). No other criteria are met or applicable. The combined evidence supports a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
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.5722_5723del
Protein Change
L1908Rfs*2
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 1908: L1908V, L1908P
Alternate Identifiers
COSM7212222
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.5722_5723del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000399%
Extremely Rare
Highest in Population
South Asian
0.00327%
Rare
Global: 0.000399%
South Asian: 0.00327%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250888Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000399%, 1/250888 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00327%, 1/30598 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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 1908: L1908V, L1908P
PM5 criterion applied.
Functional Summary
The BRCA2 L1908Rfs*2 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 disruption supports a damaging effect of the variant.
Database Previews
OncoKB
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 loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart". The evidence for this variant shows: c.5722_5723delCT (L1908Rfs*2) is a frameshift predicted to introduce a premature stop codon upstream of critical BRCA2 functional domains, consistent with LOF. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where LOF is an established disease mechanism.
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: experimental studies demonstrate that similar truncating mutations in BRCA2 impair nuclear localization and homologous recombination, supporting a damaging effect. Therefore, this criterion is applied at Strong strength because well-established functional assays demonstrate a damaging effect on BRCA2.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer) and gnomAD v3.1 (non-cancer)". The evidence for this variant shows: it is present in gnomAD (MAF=0.000399%), not absent. Therefore, PM2 is not applied because the variant is observed in population controls.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 (PTC) 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: exon location is unavailable, so it cannot be determined whether other pathogenic PTC variants occur in the same exon. Therefore, PM5 is not applied due to insufficient exon information.
PS1
PS1 (Not Applied) Strength Modified
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, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is de novo occurrence in a patient with disease and no family history. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to controls". No case–control data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is location in a mutational hot spot or critical domain without benign variation. This variant is a frameshift rather than a missense/in-frame change in a defined domain. Therefore, PM1 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Supporting/Moderate/Strong evidence for variants in trans with a pathogenic variant in recessive disorders (Fanconi Anemia)". No data on trans configuration or FA phenotype are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is protein length changes as a result of in-frame indels or stop-loss variants. This variant is a frameshift with premature truncation (covered by PVS1). Therefore, PM4 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is unconfirmed de novo occurrence. No de novo data are available. Therefore, PM6 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. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is a missense variant in a gene with low rate of benign missense variation. This variant is a frameshift. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is computational evidence supporting deleterious effect. Frameshift variants do not require in silico support. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is phenotype specificity. No phenotype data specific to BRCA2-related disease are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is a reputable source reporting the variant as pathogenic. This variant is not found in ClinVar or other databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is allele frequency >0.1% in gnomAD. The variant MAF is 0.000399%, below threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is allele frequency >0.01%. The variant MAF is 0.000399%, below threshold. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is observation in healthy adults without recessive disease features. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is well-established functional studies showing no damaging effect. Experimental data show a damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is lack of segregation in families. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is missense/in-frame variants outside critical domains. This variant is a truncating frameshift. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is observed in trans with a pathogenic variant for a dominant disorder. No such data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is in-frame indels in repetitive regions. This variant is frameshift. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is computational evidence suggesting no impact. The frameshift clearly impacts protein. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is variant found with another pathogenic variant without phenotype. No such data are available. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is reputable source reporting benign. No such report exists. Therefore, BP6 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. This variant is frameshift. Therefore, BP7 is not applied.