BRCA2 c.5722_5723del, p.Leu1908ArgfsTer2
NM_000059.4:c.5722_5723del
COSMIC ID: COSM7212222
Pathogenic
The BRCA2 c.5722_5723del (p.L1908Rfs*2) variant produces a truncating frameshift in a gene with established loss-of-function disease mechanism, is supported by strong functional evidence and absence from population databases (PVS1, PS3, PM2), and meets 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.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
No evidence of other pathogenic variants at position 1908 in gene BRCA2
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
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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
No evidence of other pathogenic variants at position 1908 in gene BRCA2
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 studies indicate 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 impairment 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." The evidence for this variant shows: c.5722_5723del causes a frameshift leading to p.L1908Rfs*2, truncating the protein well upstream of the last exon and removing critical functional domains, consistent with LOF. Therefore, this criterion is applied at Very Strong strength because the variant is a null frameshift in BRCA2, a gene with established LOF mechanism.
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 (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1))." The evidence for this variant shows: it is a frameshift, not a missense substitution matching a known pathogenic amino acid change. 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 segregation data are 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: experimental studies demonstrate that the L1908Rfs*2 truncation disrupts nuclear localization and abolishes critical DNA binding domains required for homologous recombination. Therefore, this criterion is applied at Strong strength because validated functional assays support a damaging effect.
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 the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4." The evidence for this variant shows: 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, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." The evidence for this variant shows: it is a truncating variant not assessed by domain hotspot criteria. 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 an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer)." The evidence for this variant shows: observed at MAF=0.000399% (1/250888 alleles) with no homozygotes. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in large population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA) and co-occurrent variants in the same gene." The evidence for this variant shows: no evidence of Fanconi Anemia phenotype or compound heterozygosity. 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 deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a frameshift, 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 (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before." The evidence for this variant shows: no specific data regarding 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 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 in a gene definitively known to cause the disease." The evidence for this variant shows: no family segregation data. 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 a low rate of benign missense variation and where missense variants are a common mechanism of disease." 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: "Supporting Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a clinically important functional domain and predicted impact via protein change or for predicted splicing." The evidence for this variant shows: it is a frameshift, for which in silico tools are not applicable. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting Breast cancer is very common and has high genetic heterogeneity; use only with multifactorial likelihood data." The evidence for this variant shows: no multifactorial clinical data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic but evidence not available for independent evaluation." The evidence for this variant shows: no such reports in databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD." The evidence for this variant shows: MAF is 0.000399%, well below the BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001)." The evidence for this variant shows: MAF is 0.000399%, below the BS1 threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype." The evidence for this variant shows: no unaffected homozygotes or phenotype data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." 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: "Strong Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Strong Apply BP1_Strong for silent substitution, missense or in-frame variants outside a clinically important functional domain AND no splicing predicted." The evidence for this variant shows: it is a frameshift. 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 a pathogenic variant for a fully penetrant dominant gene/disorder." The evidence for this variant shows: no 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 deletions/insertions in a repetitive region without a 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: "Supporting Missense or in-frame variants inside a clinically important functional domain and no predicted impact via protein change or splicing (BayesDel no-AF score ≤0.18 AND SpliceAI ≤0.1)." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Strong Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data." The evidence for this variant shows: no co-observation data. 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 variant as benign but evidence not available for independent evaluation." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Silent variant inside a clinically important functional domain, IF BP4 met; intronic variants outside conserved motifs IF BP4 met." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.