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"This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -56 bp |
| Donor Loss (DL) | 0.0 | 376 bp |
| Acceptor Gain (AG) | 0.0 | 190 bp |
| Donor Gain (DG) | 0.0 | 21 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies to null variants (nonsense, frameshift, canonical ±1/2 splice sites, initiation codon loss, or multi‐exon deletions) in BRCA2. The variant NM_000059.4:c.7064A>G is a missense change (E2355G), not a null variant. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies when the same amino acid change as a previously established pathogenic variant is observed. There is no pathogenic BRCA2 variant reported at codon 2355 changing glutamic acid to glycine. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence with maternity and paternity testing. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 requires well‐established functional studies demonstrating a damaging effect. No functional studies exist for E2355G. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 requires significant enrichment in cases versus controls (OR≥4, p≤0.05). No case‐control or prevalence data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to variants within a clinically important functional domain (PALB2 binding aa10-40 or DNA binding aa2481-3186). E2355 lies outside these domains. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, "PM2 Supporting: Absent from controls in an outbred population, from gnomAD v2.1 and v3.1." The variant is not observed in gnomAD or other population databases. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, PM3 applies to co-occurrence in trans with a pathogenic variant in a BRCA2 Fanconi anemia phenotype. No such phenotype or biallelic data are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to protein length changes due to in‐frame indels or stop‐loss variants. E2355G is a missense variant. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 applies when a novel missense change occurs at an amino acid where a different pathogenic missense change is known. No pathogenic missense changes at codon 2355 are reported. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation. No de novo data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 applies to co-segregation in affected family members. Segregation data are not available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies when missense variants are a common mechanism of disease in the gene. BRCA2 is primarily associated with loss‐of‐function variants; missense is not a predominant mechanism. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 applies for computational evidence of deleterious effect (BayesDel no-AF ≥0.30 or SpliceAI ≥0.2). In silico tools predict benign/tolerated and SpliceAI=0.01. Therefore, PP3 is not applied, and BP4 is used instead.
PP4 (Not Applied)
According to VCEP guidelines, PP4 applies to specific clinical phenotype likelihood models. No multifactorial likelihood data are available. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies to reported pathogenic assertions from reputable sources without primary evidence. ClinVar entries report this variant as VUS, not pathogenic. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies for allele frequency >0.1% in gnomAD non-founder populations. The variant is absent. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies for filter allele frequency >0.01%. The variant is absent. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies for observation in healthy adults without Fanconi anemia. No such data are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires well‐established functional studies showing no damaging effect. None exist. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 applies to lack of segregation in affected family members. No segregation studies are available. Therefore, BS4 is not applied.
BP1 (Strong)
According to VCEP guidelines, "BP1_Strong: silent or missense variants outside a clinically important functional domain AND no splicing predicted (SpliceAI≤0.1)." E2355G is a missense variant outside BRCA2 functional domains with SpliceAI=0.01. Therefore, BP1 is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies to observation in cis with a pathogenic variant for a dominant disorder. No co-occurrence data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in‐frame indels in repetitive regions. E2355G is a missense change. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, "BP4 Supporting: missense variants inside a functional domain with no predicted impact or intronic variants outside splice sites with no predicted impact." Multiple in silico tools predict benign impact and SpliceAI=0.01. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, BP5 applies to co-observation with a pathogenic variant in a gene with no specific phenotype. No such observations are reported. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies to reputable source assertions of benign impact without evidence. No such benign assertions exist. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 applies to silent or intronic variants with no splicing impact. E2355G is missense. Therefore, BP7 is not applied.