Submissions for variant NM_007294.4(BRCA1):c.1934C>A (p.Ser645Tyr)

gnomAD frequency: 0.00001  dbSNP: rs80357129

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047645	SCV000075658	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 645 of the BRCA1 protein (p.Ser645Tyr). This variant is present in population databases (rs80357129, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 18273839, 19491284, 23593081, 25415331, 27062684, 30702160). This variant is also known as 2053C-A (S645Y). ClinVar contains an entry for this variant (Variation ID: 54404). 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 with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000129530	SCV000184306	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	The p.S645Y variant (also known as c.1934C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 1934. The serine at codon 645 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration has been identified in individuals with personal and/or family history of breast and/or ovarian cancer (Haffty BG et al. Ann. Oncol., 2009 Oct;20:1653-9; Ou J et al. J Breast Cancer, 2013 Mar;16:50-4; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Kim YC et al. Oncotarget, 2016 Feb;7:9600-12; Zuntini R et al. Front Genet, 2018 Sep;9:378). Additionally, this alteration was not found to have a significant impact on splicing in a study utilizing a minigene assay (Anczuków O et al. Genes Chromosomes Cancer, 2008 May;47:418-26). 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 this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000129530	SCV000912045	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine at codon 645 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals affected with breast cancer (PMID: 19491284, 23593081, 25415331) and in hereditary breast and ovarian cancer families (PMID: 18273839, 27062684, 30702160). This variant has been identified in 3/250944 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001731343	SCV001983923	uncertain significance	not provided	2021-04-21	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; Also known as 2053C>A; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Casadei 2001, Haffty 2009, Ou 2013, Bolognesi 2014, Azzollini 2016, Kim 2016, Zuntini 2018); This variant is associated with the following publications: (PMID: 27062684, 25415331, 18273839, 16518693, 30254663, 30702160, 26848529, 23593081, 19491284, 11556835, 31825140)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129530	SCV003849619	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111735	SCV000144253	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1997-11-14	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496441	SCV000587169	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Department of Medical and Surgical Sciences, University of Bologna	RCV000111735	SCV004228338	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)