Submissions for variant NM_007294.4(BRCA1):c.124A>C (p.Ile42Leu)

dbSNP: rs80357163

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482375	SCV000571897	uncertain significance	not provided	2016-10-05	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.124A>C at the cDNA level, p.Ile42Leu (I42L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATA>CTA). Using alternate nomenclature, this variant would be defined as BRCA1 243A>C. This variant was observed in a pediatric patient with T-cell acute lymphoblastic leukemia (Zhang 2015). BRCA1 Ile42Leu 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 Isoleucine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ile42Leu occurs at a position that is conserved in mammals and is located within the RING domain as well as the BRD7 and BARD1 binding domains (Narod, 2004, Borg 2010, Harte 2010, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ile42Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482375	SCV001470157	uncertain significance	not provided	2019-11-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002402411	SCV002674462	likely benign	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV001072500	SCV005402513	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-04-12	criteria provided, single submitter	curation	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).In brief, for BRCA1 variants, if a variant was categorized as FUNC (functional), it was assigned BS3 evidence and no PS3 evidence, whereas if it was categorized as LOF (loss of function), the variant was assigned PS3 evidence and no BS3 evidence. Variants categorized as INT (intermediate) were left unannotated. For the BRCA1 combining criteria, greater than or equal to 1 criteria of strong benign evidence was enough to reclassify the VUS as Likely Benign. This variant GRCh38:17:43115736:T>G was assigned evidence codes ['BS3'] and an overall classification of Likely benign
All of Us Research Program, National Institutes of Health	RCV004802072	SCV005428672	uncertain significance	BRCA1-related cancer predisposition	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 42 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. unctional studies have reported that this variant does not impact BRCA1 function in a haploid cell proliferation, a yeast and a mammalian two-hybrid BARD1 binding and an E3 ubiquitin ligase assay (PMID: 25823446, 30209399, 35659930). To our knowledge, this variant has not been reported in individuals affected with BRCA1-related disorders in the literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005056055	SCV005723855	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 42 of the BRCA1 protein (p.Ile42Leu). 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: 422425). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative 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.
Brotman Baty Institute, University of Washington	RCV001072500	SCV001237891	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro