Submissions for variant NM_007294.4(BRCA1):c.1322T>C (p.Ile441Thr)

dbSNP: rs1163497041

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001011013	SCV001171290	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-03	criteria provided, single submitter	clinical testing	The p.I441T variant (also known as c.1322T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 1322. The isoleucine at codon 441 is replaced by threonine, an amino acid with similar properties. This alteration was observed with an allele frequency of 0.00028 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00036 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083). 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.
Color Diagnostics, LLC DBA Color Health	RCV001011013	SCV001357149	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-21	criteria provided, single submitter	clinical testing
Invitae	RCV001218808	SCV001390712	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-22	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: 818924). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823, 30415210). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 441 of the BRCA1 protein (p.Ile441Thr).
University of Washington Department of Laboratory Medicine, University of Washington	RCV001011013	SCV003846014	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).