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

gnomAD frequency: 0.00001  dbSNP: rs397508904

Total submissions: 6

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	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-15	criteria provided, single submitter	clinical testing	The p.P58A variant (also known as c.172C>G), located in coding exon 3 of the BRCA1 gene, results from a C to G substitution at nucleotide position 172. The proline at codon 58 is replaced by alanine, an amino acid with highly similar properties. This alteration was seen in a Chinese patient who was diagnosed with breast cancer at 55 and who had two sisters with ovarian cancer. Study authors noted that the alteration was absent in at least 50 control individuals and classified it as deleterious (Ang P et al. Cancer Epidemiol. Biomarkers Prev. 2007 Nov;16:2276-84). Another study identified the p.P58A variant in a hereditary breast/ovarian cancer (HBOC) Italian family; however, clinical details were not provided, and the authors classified it is a variant of unknown significance (Seymour IJ et al. Breast Cancer Res. Treat. 2008 Nov;112:343-9). Additionally, a functional assay measuring BRCA1 E3 ubiquitin ligase activity demonstrated that p.P58A had slightly better activity than wild type (Starita LM et al. Genetics. 2015 Jun;200:413-22). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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.
Invitae	RCV001314278	SCV001504805	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-01	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.
Brotman Baty Institute, University of Washington	RCV001077107	SCV001242980	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro