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
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The BRCA1 V660Sfs*41 variant is a truncating mutation that likely results in loss of BRCA1 protein function. Functional evidence indicates that truncating mutations in BRCA1 can lead to aberrant protein folding, impaired DNA damage response, and elevated levels of aneuploidy in human breast cancer cell lines. Additionally, these mutations can cause aberrant protein localization, affecting interactions with binding partners. Mouse models with BRCA1 truncating mutations develop various cancers, supporting the damaging effect of such mutations.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 49 bp |
| Donor Loss (DL) | 0.0 | 303 bp |
| Acceptor Gain (AG) | 0.0 | -5 bp |
| Donor Gain (DG) | 0.0 | -33 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
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 (LOF) is a known mechanism of disease." The evidence for this variant shows: c.1977del is a frameshift predicted to introduce a premature stop codon and cause loss of BRCA1 function. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in a gene where LOF is a known mechanism of disease.
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." The evidence for this variant shows: it is a frameshift, not a missense substitution. Therefore, this criterion is not applied because the variant type does not meet PS1 requirements.
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." The evidence for this variant shows: no de novo occurrence has been reported. Therefore, this criterion is not applied because there is no de novo evidence.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: functional assays of truncating BRCA1 variants demonstrate loss of DNA repair function, aberrant folding, and tumorigenesis in models. Therefore, this criterion is applied at Strong strength because well-established functional studies support a damaging effect.
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 (case-control studies; p≤0.05 and OR≥4)." The evidence for this variant shows: no published case-control data. Therefore, this criterion is not applied due to lack of case-control evidence.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Moderate Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: it is a frameshift variant, not a missense variant within a defined functional domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 and gnomAD v3.1." The evidence for this variant shows: it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Apply for patient with phenotype consistent with BRCA1-related Fanconi Anemia and co-occurring variants in the same gene." The evidence for this variant shows: no Fanconi Anemia phenotype or trans configuration data. 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 for this variant shows: it is a frameshift causing LOF, which is covered by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Protein termination codon variant in an exon where a different proven pathogenic termination codon variant has been seen." The evidence for this variant shows: no specific documentation of another proven PTC variant in the same exon. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data. 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." The evidence for this variant shows: 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 low rate of benign missense variation." The evidence for this variant shows: it is a frameshift variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting In silico predictions support a deleterious effect for missense or in-frame variants or predicted splicing impact." The evidence for this variant shows: no in silico prediction for missense or splicing impact relevant to this frameshift. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting Multifactorial likelihood clinical data in breast cancer families." The evidence for this variant shows: no multifactorial likelihood analysis data. 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." The evidence for this variant shows: not found in ClinVar. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Filter allele frequency >0.001 in gnomAD." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Filter allele frequency >0.0001 in gnomAD." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Applied in absence of features of recessive disease (Fanconi Anemia phenotype)." The evidence for this variant shows: no homozygous individuals reported but no FA phenotype data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established in vitro/in vivo functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 is: "Strong Silent, missense or in-frame variant outside a functional domain with no predicted splicing impact." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant in dominant disorder or in cis with a pathogenic variant in recessive disorder without phenotype." The evidence for this variant shows: no such data. 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 a known function." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting No predicted impact via protein change or splicing for missense/in-frame or intronic variants." The evidence for this variant shows: not applicable to frameshift. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting Co-occurrence with pathogenic variant in another gene without specific phenotype." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The evidence for this variant shows: none reported as benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Silent variant with no predicted splicing impact or intronic variant outside splice sites." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.