Submissions for variant NM_007294.4(BRCA1):c.5101C>A (p.Leu1701Met)

gnomAD frequency: 0.00001  dbSNP: rs910555398

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469376	SCV000549265	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1701 of the BRCA1 protein (p.Leu1701Met). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 409300). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586375	SCV000699201	uncertain significance	not provided	2016-08-29	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5101C>A (p.Leu1701Met) variant involves the alteration of a conserved nucleotide. Leu1701 is a conserved amino acid located in the BRCT domain, and 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120448 control chromosomes, and has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000775750	SCV000910184	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775750	SCV002642476	likely benign	Hereditary cancer-predisposing syndrome	2021-12-03	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.
All of Us Research Program, National Institutes of Health	RCV001072254	SCV004817591	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV001072254	SCV005402481	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 GRCh38:17:43063925:G>T was assigned evidence codes ['BS3', 'BP4'] and an overall classification of Likely benign
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586375	SCV005626132	uncertain significance	not provided	2023-12-27	criteria provided, single submitter	clinical testing	The BRCA1 c.5101C>A (p.Leu1701Met) variant, to the best of our knowledge, has not been reported in individuals with BRCA1-related conditions in the published literature. Experimental studies indicate this variant has neutral effects on BRCA1 protein expression and transcriptional activation activity, however the effects of this variant on homology-directed DNA repair were conflicting (PMIDs: 37085799 (2023), 30209399 (2018)). The frequency of this variant in the general population, 0.000032 (1/31392 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Brotman Baty Institute, University of Washington	RCV001072254	SCV001237601	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro