ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3965A>C (p.Lys1322Thr) (rs80357042)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164572 SCV000215230 uncertain significance Hereditary cancer-predisposing syndrome 2015-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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.
Invitae RCV000696194 SCV000824746 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-02-19 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 1322 of the BRCA1 protein (p.Lys1322Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 185202). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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