Submissions for variant NM_007294.4(BRCA1):c.3065C>T (p.Thr1022Ile)

dbSNP: rs786202070

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164701	SCV000215369	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-27	criteria provided, single submitter	clinical testing	The p.T1022I variant (also known as c.3065C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3065. The threonine at codon 1022 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not 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.
Counsyl	RCV000409623	SCV000489094	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-08-17	criteria provided, single submitter	clinical testing
Invitae	RCV000470286	SCV000549360	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1022 of the BRCA1 protein (p.Thr1022Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 185304). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000164701	SCV000909321	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1022 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800487	SCV002046612	uncertain significance	not specified	2021-01-25	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164701	SCV003849150	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).