Submissions for variant NM_007294.4(BRCA1):c.1424G>T (p.Ser475Ile)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002391901	SCV002697385	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-19	criteria provided, single submitter	clinical testing	The p.S475I variant (also known as c.1424G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 1424. The serine at codon 475 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 225000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.S475I remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002391901	SCV003851306	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).