Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000059.4 | MANE Select | 11954 nt | 200–10456 |
| NM_000059.2 | Alternative | 11386 nt | 228–10484 |
| NM_000059.3 | RefSeq Select | 11386 nt | 228–10484 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The BRCA2 I332M variant has not been functionally characterized. In silico studies provide inconclusive evidence regarding its effect on protein function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 209 bp |
| Donor Loss (DL) | 0.0 | -30 bp |
| Acceptor Gain (AG) | 0.0 | -48 bp |
| Donor Gain (DG) | 0.0 | 208 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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 it is a missense change (I332M), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
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)." The evidence for this variant shows no previously established pathogenic variant with the same amino acid change (I332M). Therefore, this criterion is not applied.
PS2 (Not Applied)
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." There are no data on de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect." No functional studies exist for BRCA2 I332M. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong: The prevalence of the variant in affected individuals is significantly increased compared to controls (p≤0.05, OR≥4)." No case-control data are available for this variant. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Moderate: Variant located in a mutational hot spot and/or critical functional domain without benign variation." The I332M change lies outside of defined BRCA2 functional domains (PALB2-binding aa10–40 and DNA-binding aa2481–3186). Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent from controls in gnomAD v2.1 and v3.1 (non-cancer)." The evidence for this variant shows it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Apply for BRCA1/2-related Fanconi Anemia phenotype with co-occurring variants, based on point system." No Fanconi Anemia phenotype or co-occurrence data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." This variant is a single amino acid substitution without length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 applies only to protein termination codon (PTC) variants in exons with known PTC pathogenic variants. I332M is a missense variant, not a PTC. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity/maternity." No de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting: Co-segregation with disease in multiple affected family members." No family segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation where missense variants are a common mechanism of disease." BRCA2 has a high rate of both pathogenic and benign missense variants. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting: Predicted impact via protein change (BayesDel no-AF ≥0.30) or splicing (SpliceAI ≥0.2)." The evidence shows SpliceAI=0 and BayesDel no-AF unknown but in silico mixed; criteria for PP3 are not met. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Use only to capture combined LR toward pathogenicity based on phenotype specificity." No specific phenotype or multifactorial likelihood data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source with pathogenic classification but without available evidence." No such source exists for this variant. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Filter allele frequency >0.1% in gnomAD." This variant is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: Filter allele frequency >0.01% in gnomAD." This variant is absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Applied in absence of recessive disease features (Fanconi Anemia) in healthy individuals." No data on healthy adult carriers are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-established functional studies show no damaging effect." No functional studies exist. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong: Lack of segregation in affected family members." No segregation data are available. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines, the rule for BP1 is: "Strong: Apply BP1_Strong for silent substitution, missense or in-frame indels outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)." The I332M change is a missense variant at residue 332, outside defined functional domains (aa10–40 and 2481–3186), with SpliceAI=0 predicting no splicing impact. Therefore, this criterion is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene." No trans co-occurrence data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to VCEP guidelines, the rule for BP3 is: "Strong for in-frame indels in repetitive regions without known function." This variant is a missense change, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense variants inside a functional domain with no predicted impact via protein change (BayesDel ≤0.18) and no splicing (SpliceAI ≤0.1)." The I332M variant lies outside functional domains. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Use only to capture combined LR against pathogenicity based on multifactorial likelihood in co-observed cases." No such data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source with benign classification but without evidence." No such source exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: Silent or intronic variants outside conserved splice sites with no splicing impact, OR missense inside domain if BS3 met." This variant is missense outside domain and BS3 is not met. Therefore, this criterion is not applied.