Submissions for variant NM_007294.4(BRCA1):c.80G>A (p.Cys27Tyr)

dbSNP: rs1064793052

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001027178	SCV001189692	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	The p.C27Y variant (also known as c.80G>A), located in coding exon 1 of the BRCA1 gene, results from a G to A substitution at nucleotide position 80. The cysteine at codon 27 is replaced by tyrosine, an amino acid with highly dissimilar properties. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This alteration has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Liang Y et al. Med. Sci. Monit. 2018 Apr;24:2465-2475; Machackova E et al. Klin Onkol, 2019;32:51-71; Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049303	SCV001213348	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-09-23	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). 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. This variant disrupts the c.80G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 11526114, 22843421, 30209399). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and/or protein function (PMID: 30209399). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with breast cancer (PMID: 29681614). This sequence change replaces cysteine with tyrosine at codon 27 of the BRCA1 protein (p.Cys27Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant also falls at the last nucleotide of exon 2 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon.
Breast Center, Key Laboratory of Carcinogenesis and Translational Research	RCV001049303	SCV001430312	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Brotman Baty Institute, University of Washington	RCV001077721	SCV001243693	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
PreventionGenetics, part of Exact Sciences	RCV004554845	SCV004720744	likely pathogenic	BRCA1-related disorder	2023-11-09	no assertion criteria provided	clinical testing	The BRCA1 c.80G>A variant is predicted to result in the amino acid substitution p.Cys27Tyr. This variant has been reported in multiple individuals with breast cancer (Table 5, Liang et al. 2018. PubMed ID: 29681614; Table 3, Machackova et al. 2019. PubMed ID: 31409081). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An in vitro experimental study suggests variants that affect p.Cys27 impact protein function (Table S1, Findlay et al. 2018. PubMed ID: 30209399). This variant has been classified as likely pathogenic by other institutions in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/827453/). This variant is interpreted as likely pathogenic.