Submissions for variant NM_007294.4(BRCA1):c.4268G>T (p.Ser1423Ile)

dbSNP: rs876660129

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213257	SCV000277299	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	The p.S1423I variant (also known as c.4268G>T), located in coding exon 11 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4268. The serine at codon 1423 is replaced by isoleucine, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759538	SCV000888916	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in a large breast cancer association study in a healthy individual (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA1). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Invitae	RCV001053716	SCV001217992	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-18	criteria provided, single submitter	clinical testing	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: 233009). 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 serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1423 of the BRCA1 protein (p.Ser1423Ile).
Illumina Laboratory Services, Illumina	RCV001124851	SCV001283849	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000759538	SCV001874855	uncertain significance	not provided	2021-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 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 4387G>T; This variant is associated with the following publications: (PMID: 15343273, 22737296, 19369211, 27535533)