Submissions for variant NM_007294.4(BRCA1):c.2444T>C (p.Ile815Thr)

dbSNP: rs730881484

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159970	SCV000210132	uncertain significance	not provided	2014-10-17	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2444T>C at the cDNA level, p.Ile815Thr (I815T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ile815Thr 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. This variant is a non-conservative substitution in which a neutral non-polar amino acid is replaced with a neutral polar one, altering a position that is highly variable throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider BRCA1 Ile815Thr to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515109	SCV003026263	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-16	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 182148). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 815 of the BRCA1 protein (p.Ile815Thr). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157424	SCV003847667	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).