Submissions for variant NM_007294.4(BRCA1):c.3355A>T (p.Thr1119Ser)

gnomAD frequency: 0.00003  dbSNP: rs80356949

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048162	SCV000076175	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1119 of the BRCA1 protein (p.Thr1119Ser). This variant is present in population databases (rs80356949, gnomAD 0.0009%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 35171259). ClinVar contains an entry for this variant (Variation ID: 54855). 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	RCV000129260	SCV000184020	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-29	criteria provided, single submitter	clinical testing	The p.T1119S variant (also known as c.3355A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 3355. The threonine at codon 1119 is replaced by serine, an amino acid with similar properties. This alteration has been detected in two individuals with a personal and/or family history of breast and/or ovarian cancer (Judkins T et al. Cancer Res. 2005 Nov 1;65(21):10096-103 and Brianese R et al. Breast Cancer Res Treat. 2018 Feb;167(3):803-814). This amino acid position is poorly 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.
GeneDx	RCV000235634	SCV000292918	uncertain significance	not provided	2020-08-17	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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16267036, 31131967)
Color Diagnostics, LLC DBA Color Health	RCV000129260	SCV000906799	likely benign	Hereditary cancer-predisposing syndrome	2016-09-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235634	SCV001133550	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/250290 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported with other pathogenic BRCA1/BRCA2 variants in individuals who were affected or suspected of having a BRCA related disease (BIC (https://research.nhgri.nih.gov/bic/) and PMID: 16267036 (2005)). In a large breast cancer association study, the variant was reported in one individual with breast cancer (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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129260	SCV003852077	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)	RCV000112078	SCV000144735	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing