Submissions for variant NM_007294.4(BRCA1):c.3965A>C (p.Lys1322Thr)

gnomAD frequency: 0.00001  dbSNP: rs80357042

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164572	SCV000215230	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	The p.K1322T variant (also known as c.3965A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 3965. The lysine at codon 1322 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000757034	SCV000570153	uncertain significance	not provided	2016-04-29	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.3965A>C at the cDNA level, p.Lys1322Thr (K1322T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). Using alternate nomenclature, this variant would be defined as BRCA1 4084A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Lys1322Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Lys1322Thr occurs at a position that is not conserved and is located in the SCD domain as well as a region known to interact with multiple other proteins (Chen 1998, Narod 2004, Clark 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Lys1322Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696194	SCV000824746	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1322 of the BRCA1 protein (p.Lys1322Thr). 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: 185202). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 80%. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757034	SCV000885072	uncertain significance	not provided	2018-02-07	criteria provided, single submitter	clinical testing	The BRCA1 c.3965A>C; p.Lys1322Thr variant (rs80357042), to our knowledge, is not reported in the medical literature but is classified as uncertain in ClinVar (Variation ID: 185202). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The lysine at codon 1322 is moderately conserved but computational algorithms (SIFT: Damaging, PolyPhen2: Benign) predict conflicting effects of this variant on the protein. Due to limited information, the clinical significance of the p.Lys1322Thr variants is uncertain at this time.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164572	SCV003849377	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).