Submissions for variant NM_007294.4(BRCA1):c.2897T>C (p.Ile966Thr)

gnomAD frequency: 0.00002  dbSNP: rs879254045

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759511	SCV000293275	uncertain significance	not provided	2015-10-20	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2897T>C at the cDNA level, p.Ile966Thr (I966T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). Using alternate nomenclature, this variant would be defined as BRCA1 3016T>C. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRCA1 Ile966Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ile966Thr occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Ile966Thr is pathogenic or benign.
Ambry Genetics	RCV000566390	SCV000665828	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-25	criteria provided, single submitter	clinical testing	The p.I966T variant (also known as c.2897T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 2897. The isoleucine at codon 966 is replaced by threonine, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759511	SCV000888876	uncertain significance	not provided	2018-07-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779905	SCV000916810	uncertain significance	not specified	2018-10-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2897T>C (p.Ile966Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 121300 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2897T>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000792554	SCV000931858	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-25	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: 246006). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 966 of the BRCA1 protein (p.Ile966Thr).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000566390	SCV003849273	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).