Submissions for variant NM_007294.4(BRCA1):c.5242G>T (p.Gly1748Cys)

dbSNP: rs397507245

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473758	SCV000549323	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-20	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.Gly1748 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16644204, 24845084, 28781887, 30209399, 31131967). 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, 30765603). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 37650). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. 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 1748 of the BRCA1 protein (p.Gly1748Cys).
GeneDx	RCV000487391	SCV000566826	uncertain significance	not provided	2015-06-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5242G>T at the cDNA level, p.Gly1748Cys (G1748C) at the protein level, and results in the change of a Glycine to a Cysteine (GGT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 5361G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gly1748Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly1748Cys occurs at a position that is conserved across species and is located within a region containing the BRCT domains (Narod 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Gly1748Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509724	SCV000608118	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-31	criteria provided, single submitter	clinical testing	The p.G1748C variant (also known as c.5242G>T), located in coding exon 18 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5242. The glycine at codon 1748 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is functionally deleterious in a haploid cell survival assay as well as a transcription activation assay (Findlay GM et al. Nature, 2018 10;562:217-222; Fernandes VC et al. J Biol Chem 2019 Apr;294(15):5980-5992.). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is within an alpha-helix and is expected to result in a decrease in structural stability (Ambry internal data). In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031231	SCV000053831	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2011-09-15	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031231	SCV001242461	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro