Submissions for variant NM_007294.4(BRCA1):c.116G>T (p.Cys39Phe)

dbSNP: rs80357498

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206829	SCV000259445	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 39 of the BRCA1 protein (p.Cys39Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28888541, 29446198, 33278427). ClinVar contains an entry for this variant (Variation ID: 37393). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). This variant disrupts the p.Cys39 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9808526, 11320250, 12827452, 19543972, 21725363, 21922593, 21990134, 22843421, 23161852, 24489791). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000030974	SCV000324975	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509711	SCV000607989	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-05	criteria provided, single submitter	clinical testing	The p.C39F variant (also known as c.116G>T), located in coding exon 2 of the BRCA1 gene, results from a G to T substitution at nucleotide position 116. The cysteine at codon 39 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This nucleotide substitution was non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222), and demonstrated impaired BARD1 binding and E3 Ubiquitin Ligase activity (Starita LM et al. Genetics, 2015 Jun;200:413-22). Additionally, codon 39 is located in a critical region of the BRCA1 protein RING domain. Multiple alterations at this codon, including p.C39R, p.C39Y, and p.C39S have been shown to alter the structure of the RING domain and negatively impact protein function and binding (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9; Brzovic PS et al. Proc Natl Acad Sci USA. 2003 May;100(10):5646-51; Ransburgh DJ et al. Cancer Res. 2010 Feb 1;70(3):988-95; Sweet K et al. Breast Cancer Res Treat. 2010 Feb;119(3):737-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798024	SCV002043419	likely pathogenic	Breast and/or ovarian cancer	2022-01-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509711	SCV004361135	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 39 in the RING domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this mutant protein has decreased ubiquitin protein ligase activity and is deficient in BARD1 binding, and is predicted to be non-functional for homology-directed DNA repair (PMID: 25823446, 30219179). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with breast cancer (PMID: 33278427), and has been identified in one family among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.115T>A (p.Cys39Ser), c.115T>C (p.Cys39Arg), c.115T>G (p.Cys39Gly), c.116G>A (p.Cys39Tyr), and c.117T>G (p.Cys39Trp) are considered to be disease-causing (ClinVar variation ID: 54151, 54152, 54153, 37392, 267497), supporting that the cysteine at this position is important for protein function. Based on the available evidence, this variant is classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000030974	SCV000053565	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-12-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000030974	SCV001242368	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV000030974	SCV004244194	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing