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 (8 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
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 ...). Apply at appropriate strength according to PVS1 flowchart." The evidence for this variant shows it is a synonymous (silent) change, not predicted to introduce a null effect. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to VCEP guidelines the rule for PS1 is: "Strong Apply PS1 for missense substitutions where a previously classified pathogenic variant has the same amino acid change." The evidence for this variant shows it is a synonymous change (no amino acid alteration). Therefore, PS1 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 de novo data available for this variant. Therefore, PS2 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." No functional assay data exist for this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared to controls (p≤0.05, OR≥4)." No case-control or patient prevalence data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines the rule for PM1 is: "Located in a mutational hot spot or well‐studied functional domain without benign variation." This variant lies outside known BRCA2 functional domains. Therefore, PM1 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." The evidence for this variant shows a maximum overall MAF of 0.0179% (50/278,842 alleles) in gnomAD non-cancer. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines the rule for PM3 is: "Apply for patients with phenotype consistent with BRCA2-related Fanconi Anemia and co-occurring variants." No Fanconi Anemia phenotype or trans observations are available. Therefore, PM3 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 synonymous. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines the rule for PM5 is: "Novel missense change at an amino acid where a different pathogenic missense change has been seen." This variant is silent. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." No de novo data exist. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines the rule for PP1 is: "Co-segregation with disease in multiple affected family members (quantitative Bayes score)." No segregation data are available. Therefore, PP1 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 and pathogenic missense variants common." This variant is synonymous. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines the rule for PP3 is: "Supporting computational evidence for deleterious effect (BayesDel score≥0.30 or SpliceAI≥0.2)." SpliceAI=0 and BayesDel no-AF score not elevated. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines the rule for PP4 is: "Phenotype highly specific for a disease with single genetic etiology." No phenotype data specific for BRCA2 are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines the rule for PP5 is: "Reputable source reports variant as pathogenic." No reputable source reports pathogenic for this variant. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines the rule for BA1 is: "Filter allele frequency >0.1% in non-founder populations (FAF>0.001)." The maximum MAF is 0.0179% (0.000179), below the BA1 threshold. Therefore, BA1 is not applied.
BS1 (Strong)
According to VCEP guidelines the rule for BS1 is: "Strong Filter allele frequency (FAF)>0.0001 in gnomAD non-cancer." The evidence shows a MAF of 0.0179% overall and 0.193% in African/African American, both >0.0001. Therefore, BS1 is applied at Strong strength.
BS2 (Not Applied)
According to VCEP guidelines the rule for BS2 is: "Absence of features of recessive disease (Fanconi Anemia) in individuals with the variant." No phenotype data regarding Fanconi Anemia absence are available. Therefore, BS2 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 assay data exist. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines the rule for BS4 is: "Lack of segregation in affected family members (quantitative Bayes LR≤0.05)." No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to VCEP guidelines the rule for BP1 is: "Silent, missense or in-frame variants outside functional domains and no splicing predicted." This variant is silent but VCEP BP1 is designated for missense/in-frame. Therefore, BP1 is not applied.
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 pattern." No such observations are reported. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines the rule for BP3 is: "In-frame indels in repetitive regions without a known function." This variant is synonymous. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines the rule for BP4 is: "Supporting computational evidence of no impact for missense/in-frame inside domains or intronic outside splice sites." This variant is synonymous and outside defined domains; VCEP BP4 does not cover this scenario. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to VCEP guidelines the rule for BP5 is: "Observation of the variant in a case with an alternative molecular basis for disease." No such co-occurrence data are available. Therefore, BP5 is not applied.
BP6 (Supporting)
According to standard ACMG guidelines the rule for BP6 is: "Supporting Reputable source reports variant as benign." ClinVar lists this variant as Benign from 8 labs and Likely Benign from 4 labs, and ENIGMA classifies it as Benign. Therefore, BP6 is applied at Supporting strength.
BP7 (Not Applied)
According to VCEP guidelines the rule for BP7 is: "Silent or intronic variants with no predicted splice impact, with BP4 met for supporting strength or functional assay for strong." No mRNA assay data; VCEP BP4 was not applied, so BP7 is not applied.