Submissions for variant NM_007294.4(BRCA1):c.3437G>C (p.Cys1146Ser)

dbSNP: rs80357247

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770742	SCV000902225	uncertain significance	Breast and/or ovarian cancer	2017-08-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453363	SCV002615184	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-19	criteria provided, single submitter	clinical testing	The p.C1146S variant (also known as c.3437G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 3437. The cysteine at codon 1146 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002453363	SCV003848600	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Invitae	RCV003644880	SCV004517367	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1146 of the BRCA1 protein (p.Cys1146Ser). 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). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 54886).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112098	SCV000144765	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356231	SCV001551345	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Cys1146Ser variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs80357247) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by BIC). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Cys1146 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.