Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.74C>T variant in BRCA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 25 (p.Pro25Leu). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.35, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold ≤0.1) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 35659930) (PS3 met). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10580713/MONDO:0700268/092
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
This variant is denoted BRCA1 c.74C>T at the cDNA level, p.Pro25Leu (P25L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). Using alternate nomenclature, this variant would be defined as BRCA1 193C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro25Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro25Leu occurs at a position that is conserved across species and is located in the RING finger domain as well as a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro25Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
The BRCA1 p.Pro25Leu variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs876660096) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx and Foulkes Cancer Genetics).The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017).A homology directed recombination efficiency assay indicated this variant has deficient homologous recombination (Yi 2018, Ambry Genetics ACMG poster). The p.Pro25 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
BRCA1-related cancer predispositionPathogenic:1
May 23, 2025
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
Significance:Likely pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
The c.74C>T variant in BRCA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 25 (p.Pro25Leu). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.35, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold ≤0.1) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 35659930) (PS3 met). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3). -
The p.P25L variant (also known as c.74C>T), located in coding exon 1 of the BRCA1 gene, results from a C to T substitution at nucleotide position 74. The proline at codon 25 is replaced by leucine, an amino acid with similar properties. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This alteration has been identified in 1/7400 Czech families with suspected hereditary predisposition to breast and/or ovarian cancer (Machackova E et al. Klin Onkol, 2019;32:51-71). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Brzovic PS et al. Nat Struct Biol, 2001 Oct;8:833-7; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Breast and/or ovarian cancerUncertain:1
Jan 28, 2016
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Hereditary breast ovarian cancer syndromeUncertain:1
Apr 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 25 of the BRCA1 protein (p.Pro25Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 232955). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);