Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_007294.4 | MANE Select | 7088 nt | 114–5705 |
| NM_007294.2 | Alternative | 7191 nt | 201–5792 |
| NM_007294.3 | RefSeq Select | 7224 nt | 233–5824 |
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).
The BRCA1 c.3835G>A (p.Ala1279Thr) variant has been reported in the published literature in individuals/families affected with breast and/or ovarian cancer (PMIDs: 16267036 (2005), 27062684 (2016), 34658299 (2021), 38652475 (2024), 38709234 (2024)) and renal cell carcinoma (PMID: 38512353 (2024)). However, it has also been described as being likely benign in a multifactorial likelihood study (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.000035 (4/113450 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
"This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Likely benign (5 clinical laboratories) and 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) | 0.0 | -193 bp |
| Donor Loss (DL) | 0.0 | 141 bp |
| Acceptor Gain (AG) | 0.0 | -63 bp |
| Donor Gain (DG) | 0.01 | -261 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 rule: "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 variant is a missense substitution (p.Ala1279Thr) and does not create a null allele. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 rule: "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))." No previously established pathogenic variant alters amino acid 1279. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 rule: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 rule: "Well-established in vitro or in vivo functional studies supportive of a damaging effect." There are no functional studies characterizing the impact of p.Ala1279Thr. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 rule: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (p≤0.05 and OR≥4)." No case-control or enrichment data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 rule: "Apply PM1 for missense or in-frame variants inside a clinically important functional domain." The variant p.Ala1279Thr lies outside the defined BRCA1 functional domains (RING aa2–101, coiled-coil aa1391–1424, BRCT aa1650–1857). Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 (Supporting) rule: "Absent from controls in an outbred population, from gnomAD v2.1 and v3.1." The variant is extremely rare in gnomAD (MAF=0.00159%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, PM3 rule: "Apply for co-occurrence of variants in BRCA1-related Fanconi Anemia phenotype." There is no evidence of Fanconi Anemia phenotype or co-occurrence. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 rule: "Protein length changes as a result of in-frame indels or stop-loss variants." p.Ala1279Thr does not change protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 rule: "Protein termination codon variants in an exon where a different proven pathogenic PTC variant has been seen before." p.Ala1279Thr is not a termination codon variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 rule: "Assumed de novo (without confirmation of paternity/maternity)." No de novo information is available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 rule: "Co-segregation with disease in multiple affected family members (Bayes LR thresholds)." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 rule: "Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism of disease." BRCA1 missense pathogenic variants cluster in defined domains; p.Ala1279Thr lies outside these and benign variation is not unusually low. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 rule: "Apply PP3 for missense variants inside a functional domain with predicted impact (BayesDel no-AF≥0.28 or SpliceAI≥0.2)." p.Ala1279Thr lies outside key domains and in silico predictions are mixed. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 rule: "Combined clinical evidence (multifactorial likelihood) towards pathogenicity for phenotype-specific data." No likelihood ratio clinical data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 rule: "Reputable source reports variant as pathogenic." ClinVar submissions are conflicting (Benign, Likely benign, VUS). Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 rule: "Stand Alone allele frequency filter >0.1%." The variant MAF (0.00159%) is below this threshold. Therefore, this criterion is not applied.
BS1 (Supporting)
According to VCEP guidelines, BS1 (Supporting) rule: "Filter allele frequency >0.002% and ≤0.01% in gnomAD non-founder populations." The variant MAF in European non-Finnish (0.00353%) meets this. Therefore, this criterion is applied at Supporting strength.
BS2 (Not Applied)
According to VCEP guidelines, BS2 rule: "Observed in healthy adult individuals in absence of recessive disease features." No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 rule: "Well-established functional studies show no damaging effect." No such studies exist. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 rule: "Lack of segregation in affected family members (Bayes LR≤0.05)." No segregation analyses are available. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines, BP1_Strong rule: "Silent substitution, missense or in-frame insertion/deletion variants outside a clinically important functional domain AND no splicing predicted (SpliceAI≤0.1)." p.Ala1279Thr is outside defined domains and SpliceAI score is 0.01. Therefore, this criterion is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 rule: "Observed in trans with a pathogenic variant for a dominant disorder." No co-occurrence data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 rule: "In-frame deletions/insertions in repetitive regions." Not relevant to this missense change. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4 rule: "Multiple lines of computational evidence suggest no impact on gene or gene product." In silico tools (CADD, PolyPhen-2, SIFT, MetaSVM, PrimateAI) predominantly predict benign effect and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, BP5 rule: "Co-occurrence with pathogenic variant in another gene with no specific phenotype." No such co-occurrence data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 rule: "Reputable source reports variant as benign." ClinVar submissions are conflicting; no unanimous benign classification. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 rule: "Silent or intronic variants with no predicted splice impact." p.Ala1279Thr is a missense variant. Therefore, this criterion is not applied.