ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5036T>C (p.Leu1679Pro)

dbSNP: rs760038328
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000200826 SCV000254992 likely benign Hereditary breast ovarian cancer syndrome 2023-09-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023450 SCV001185330 likely benign Hereditary cancer-predisposing syndrome 2023-11-28 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.
Color Diagnostics, LLC DBA Color Health RCV001023450 SCV001346672 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-05 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 1679 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251382 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002478710 SCV002774466 uncertain significance not provided 2023-05-23 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in an individual with breast cancer (PMID: 34196900 (2021)) and characterized as likely benign in a multifactorial likelihood study (PMID: 31131967 (2019)). Additionally, a functional assay showed that this variant does not impact protein function (PMID: 30209399 (2018)). The frequency of this variant in the general population, 0.000004 (1/251382 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics RCV001076271 SCV004215130 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2023-05-14 criteria provided, single submitter clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV001076271 SCV005402486 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 GRCh38:17:43067646:A>G was assigned evidence codes ['BS3', 'BP4'] and an overall classification of Likely benign
Brotman Baty Institute, University of Washington RCV001076271 SCV001241990 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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