Submissions for variant NM_007294.4(BRCA1):c.3496G>C (p.Ala1166Pro)

dbSNP: rs745418679

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200382	SCV000254975	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-02-21	criteria provided, single submitter	clinical testing	In summary, this is a missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been published in the literature and has only been reported once in population databases (no rsID). This sequence change replaces alanine with proline at codon 1166 of the BRCA1 protein (p.Ala1166Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001770150	SCV001473956	uncertain significance	not provided	2020-01-22	criteria provided, single submitter	clinical testing	The BRCA1 c.3496G>C; p.Ala1166Pro variant (rs745418679), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 216663). This variant is found on a single chromosome in the Genome Aggregation Database (1/251294 alleles), indicating it is not a common polymorphism. The alanine at codon 1166 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Ala1166Pro variant is uncertain at this time.
GeneDx	RCV001770150	SCV002002583	uncertain significance	not provided	2021-02-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); 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 3615G>C
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157445	SCV003846628	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).
Ambry Genetics	RCV003157445	SCV004058467	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	The p.A1166P variant (also known as c.3496G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 3496. The alanine at codon 1166 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in a cohort of 524 Chinese breast cancer patients (Chen B et al. Aging (Albany NY), 2020 Feb;12:3140-3155). This amino acid position is not 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.