Submissions for variant NM_007294.4(BRCA1):c.172C>G (p.Pro58Ala)

gnomAD frequency: 0.00001  dbSNP: rs397508904

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481979	SCV000568436	uncertain significance	not provided	2016-10-26	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.172C>G at the cDNA level, p.Pro58Ala (P58A) at the protein level, and results in the change of a Proline to an Alanine (CCT>GCT). Using alternate nomenclature, this variant has been previously published as BRCA1 291C>G. This variant was observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Ang 2007, Seymour 2008). BRCA1 Pro58Ala 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 Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro58Ala occurs at a position that is not conserved and is located in the RING finger domain ubiquitination site as well as BRD7 and BARD1 interaction regions (Borg 2010, 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 Pro58Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000575682	SCV000668486	likely benign	Hereditary cancer-predisposing syndrome	2023-09-21	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	RCV000575682	SCV001351370	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-22	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 58 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. Functional studies reported this variant to be functional in homology-mediated DNA repair and a haploid cell proliferation assays (PMID: 30219179, 30209399). This variant has been reported in two hereditary breast and ovarian cancer families including at least one affected carrier (PMID: 18006916, 18092194). A multiple factorial analysis found this variant to be likely benign based on evidence including tumor pathology (PMID: 31131967). This variant has been identified in 1/31378 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314278	SCV001504805	likely benign	Hereditary breast ovarian cancer syndrome	2024-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509192	SCV002819770	uncertain significance	not specified	2022-12-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.172C>G (p.Pro58Ala) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain (IPR001841) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250812 control chromosomes (gnomAD, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.172C>G has been reported in the literature in individuals/families affected with Hereditary Breast And Ovarian Cancer Syndrome (Ang_2007, Seymour_2008, Wong_2016, Pereira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Experimental evidence evaluating an impact on protein function concluded the variant to be functional (Findlay_2018, Starita_2018, Clark_2022). Furthermore, the variant was assigned an IARC class of Likely Benign following multifactorial likelihood analysis (Parsons_2019). One ClinVar submitter (evaluation after 2014) cites the variant as likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV001077107	SCV005402509	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 GRCh38:17:43106496:G>C was assigned evidence codes ['BS3'] and an overall classification of Likely benign
Brotman Baty Institute, University of Washington	RCV001077107	SCV001242980	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro