Submissions for variant NM_007294.4(BRCA1):c.3521C>G (p.Ser1174Cys)

dbSNP: rs1055368753

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000806901	SCV000946922	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-02-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine with cysteine at codon 1174 of the BRCA1 protein (p.Ser1174Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRCA1-related disease. This variant is not present in population databases (ExAC no frequency).
Ambry Genetics	RCV001020516	SCV001182005	uncertain significance	Hereditary cancer-predisposing syndrome	2018-03-29	criteria provided, single submitter	clinical testing	The p.S1174C variant (also known as c.3521C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 3521. The serine at codon 1174 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002279542	SCV002567397	uncertain significance	not provided	2022-08-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3640C>G
University of Washington Department of Laboratory Medicine, University of Washington	RCV001020516	SCV003851768	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).