Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_007294.2 | Alternative | 7191 nt | 201–5792 |
| NM_007294.3 | RefSeq Select | 7224 nt | 233–5824 |
| NM_007294.4 | MANE Select | 7088 nt | 114–5705 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenMissense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
This missense variant replaces glutamic acid with lysine at codon 1161 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006323). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
The p.E1161K variant (also known as c.3481G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3481. The glutamic acid at codon 1161 is replaced by lysine, an amino acid with similar properties. This variant was detected in 0/143 diagnosed with breast cancer and 1/382 diagnosed with ovarian cancer (Ferreyra Y et al. Front Oncol, 2023 Aug;13:1227864). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
"This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance (1 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) | 0.02 | 89 bp |
| Donor Loss (DL) | 0.01 | -213 bp |
| Acceptor Gain (AG) | 0.01 | -417 bp |
| Donor Gain (DG) | 0.0 | 49 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 rule is: 'Very Strong Null variant (nonsense, frameshift, splice site +/–1,2, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The variant is a missense change (E1161K) not predicted to cause loss of function. Therefore, PVS1 is not applied because the variant type does not meet the rule for a null variant.
PS1 (Not Applied)
According to VCEP guidelines, PS1 rule is: 'Strong: same amino acid change as a previously classified pathogenic variant regardless of nucleotide change (no predicted effect on splicing).' No known pathogenic variant with the same E1161K amino acid change has been reported. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 rule 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, PS3 rule is: 'Strong: well-established in vitro or in vivo functional studies supportive of a damaging effect.' No functional studies have been performed for BRCA1 E1161K. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 rule is: 'Strong: prevalence of the variant in affected individuals is significantly increased compared to controls (p≤0.05, OR≥4).' No case-control or prevalence data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 rule is: 'Moderate: variant is located in a mutational hotspot or critical functional domain without benign variation.' Position 1161 lies outside defined clinically important domains (RING 2–101, coiled-coil 1391–1424, BRCT 1650–1857). Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 rule is: 'Supporting: absent from controls in an outbred population (gnomAD non-cancer).' The variant is not present in gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, PM3 rule is: 'Supporting to Strong: observed in trans with a pathogenic variant in patients with Fanconi Anemia phenotype.' No co-occurrence or FA phenotype data are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 rule is: 'Protein length changes as a result of in-frame indels or stop-loss variants.' This is a missense variant without a change in protein length. Therefore, PM4 is not applied.
PM5 (Moderate)
According to standard ACMG guidelines, PM5 rule is: 'Moderate: novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' A different pathogenic missense at residue E1161 has been reported. Therefore, PM5 is applied at Moderate strength.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 rule is: 'Supporting: assumed de novo without confirmation of paternity and maternity.' No such data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 rule is: 'Supporting to Strong: co-segregation with disease in multiple affected family members (Bayes score thresholds).' No family segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 rule is: 'Supporting: missense variant in a gene with low rate of benign missense variation where such variants are a common mechanism of disease.' Missense variants in BRCA1 are not generally the sole mechanism of disease. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 rule is: 'Supporting: missense variant inside a clinically important functional domain predicted to impact protein (BayesDel no-AF ≥0.28) or splicing (SpliceAI ≥0.2).' E1161 lies outside defined domains, and computational evidence is mixed. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 rule is: 'Supporting to Strong: detailed multifactorial clinical data (family history, pathology).' No such clinical phenotype or multifactorial analysis is available. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 rule is: 'Supporting: reputable source reports variant as pathogenic without shared evidence.' ClinVar entries report this variant as VUS. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 rule is: 'Stand Alone: allele frequency >0.1% in non-cancer gnomAD populations.' The variant is absent (MAF=0%). Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 rule is: 'Strong: allele frequency >0.01%.' The variant is absent. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 rule is: 'Strong: variant observed in healthy adults without Fanconi Anemia phenotype.' No such observations are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 rule is: 'Strong: well-established functional studies show no damaging effect.' No functional data exist. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 rule is: 'Strong: lack of segregation in affected family members.' No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to VCEP guidelines, BP1 rule is: 'Strong: silent or in-frame variants outside functional domains with no splicing impact.' This is a missense variant. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 rule is: 'Supporting: observed in trans with a pathogenic variant for a dominant disorder.' No such co-occurrence data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to VCEP guidelines, BP3 rule is: 'Strong: in-frame indels in repetitive regions without functional impact.' This is not an in-frame indel. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 rule is: 'Supporting: missense variants inside a functional domain with no predicted impact.' E1161 lies outside defined domains. Therefore, BP4 is not applied under VCEP specifications.
BP5 (Not Applied)
According to VCEP guidelines, BP5 rule is: 'Supporting: variant observed in individuals with an alternate molecular basis for disease.' No such co-occurrence data are available. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 rule is: 'Supporting: reputable source reports variant as benign without evidence.' No such report exists. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 rule is: 'Supporting: synonymous or intronic variants without splicing impact.' This is a missense variant. Therefore, BP7 is not applied.