Submissions for variant NM_007294.4(BRCA1):c.5362G>T (p.Gly1788Cys)

dbSNP: rs397509271

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563925	SCV000661077	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-08-27	criteria provided, single submitter	clinical testing	The p.G1788C variant (also known as c.5362G>T), located in coding exon 20 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5362. The glycine at codon 1788 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a Thai patient from a cohort of patients with either early-onset or family history of breast cancer (Ahmad J et al. Clin. Genet., 2012 Dec;82:594-8). Based on internal structural analysis, this p.G1788C alteration was found to cause disruption of the BRCT domain of the protein (Ambry internal data; Clapperton J et al. Nat Struct Mol Biol. 2004; 11(6):512-8). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001342446	SCV001536378	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-29	criteria provided, single submitter	clinical testing	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 p.Gly1788 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9796975, 14534301, 15689452, 16267036, 17924331, 18418466, 18512148, 20516115, 21614564, 21990134, 26689913, 27272900). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 55550). This missense change has been observed in individual(s) with breast cancer (PMID: 22486713). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1788 of the BRCA1 protein (p.Gly1788Cys).
Neuberg Centre For Genomic Medicine, NCGM	RCV001076845	SCV004048003	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The missense variant c.5425G>T (p.Gly1809Cys) in BRCA1 gene has been reported previously in a Thai patient from a cohort of patients with either earlyonset or family history of breast cancer (Ahmad J et.al., 2012). This variant has been reported to the ClinVar database as Likely Pathogenic. The p.Gly1809Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Gly at position 1809 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Gly1809Cys in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577373	SCV000679630	not provided	Familial cancer of breast		no assertion provided	literature only
Brotman Baty Institute, University of Washington	RCV001076845	SCV001242676	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro