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
OpenVariant summary: The BRCA2 c.4071A>C (p.Leu1357Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 18/120766 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0017599 (18/10228). This frequency is about 2.35 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant was reported in BrC patients without strong evidence for causality. In addition, several clinical diagnostic laboratories have classified this variant as likely benign/benign. It was also found to co-occur with a deleterious variant BRCA2 c. c.5351dup in one sample (UMD). Taken together, this variant is classified as Benign.
"This variant has been reported in ClinVar as Benign (7 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The variant BRCA2L1357= is a synonymous mutation and has not been functionally characterized.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 43 bp |
| Donor Loss (DL) | 0.0 | -225 bp |
| Acceptor Gain (AG) | 0.0 | 13 bp |
| Donor Gain (DG) | 0.0 | 130 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 loss of function is a known mechanism of disease." The evidence shows this variant is a synonymous (silent) substitution, not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
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 shows this variant is synonymous and does not change the protein. 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 is no evidence of de novo occurrence. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect are required." The evidence shows no functional studies demonstrating a damaging effect for this synonymous variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls (p ≤0.05 and OR ≥4)." There is no case–control data available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well‐established functional domain without benign variation." The evidence shows this variant is outside known functional domains. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Absent from controls in an outbred population (gnomAD v2.1 non‐cancer exome, gnomAD v3.1 non‐cancer)." The evidence shows the variant is present in gnomAD (MAF=0.000179), not absent. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 (Supporting/Moderate/Strong) is: "Apply for BRCA1/2-related Fanconi Anemia phenotype with co-occurring variants." There is no evidence of Fanconi Anemia phenotype or co-occurring variants. 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." The evidence shows this variant is synonymous. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Protein termination codon variant in an exon where a different proven pathogenic PTC has been seen before." The evidence shows this variant is synonymous, not a stop‐gain. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "De novo (without confirmation of paternity/maternity)." There is no evidence for an unconfirmed de novo event. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members (Bayes LR thresholds)." There is no segregation data. 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 a low rate of benign missense variation." The evidence shows this variant is synonymous. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 (Supporting) is: "Predicted impact via protein (BayesDel ≥0.30) or splicing (SpliceAI ≥0.2)." The evidence shows SpliceAI=0 and no protein change. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Phenotype data contributes combined likelihood ratios for pathogenicity in a heterogeneous disorder." No patient phenotype data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence shows the variant is reported as benign. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: FAF >0.001 in gnomAD non‐cancer populations." The evidence shows MAF=0.000179, which is below 0.001. Therefore, this criterion is not applied.
BS1 (Strong)
According to VCEP guidelines, the rule for BS1 is: "Strong: Filter allele frequency (FAF) >0.0001 in gnomAD v2.1/v3.1 non‐cancer populations." The evidence shows MAF=0.000179 (>0.0001). Therefore, this criterion is applied at Strong strength.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Applied in absence of features of recessive disease (Fanconi Anemia)." There is no data regarding Fanconi Anemia phenotype in carriers. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect." No functional studies are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in families (Bayes LR ≤0.05)." No segregation data are available. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines, the rule for BP1_Strong is: "Silent substitution, missense or in-frame indel outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)." The evidence shows the variant is synonymous at aa 1357 (outside domains 10–40 and 2481–3186) with SpliceAI=0. 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 dominant disorder or in cis with a pathogenic variant in any inheritance." No such observations are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in a repetitive region without known function." This is not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense/in-frame inside domain with no impact OR silent inside domain with no splicing OR intronic outside splice sites with no splicing." This variant is silent outside domains, not intronic. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Observed in a case with an alternate molecular basis for disease." There is no such case. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." The evidence shows multiple ClinVar labs and ENIGMA classify this variant as benign/likely benign. Therefore, this criterion is applied at Supporting strength.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Silent variant inside a functional domain, if BP4 met, OR intronic outside conserved motif positions if BP4 met." This silent variant is outside functional domains and BP4 is not met. Therefore, this criterion is not applied.