ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs80356949
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Total submissions: 7
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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 2021-09-05 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

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