ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1016A>C (p.Lys339Thr) (rs587781737)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129938 SCV000184757 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000587998 SCV000210097 uncertain significance not provided 2015-07-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1016A>C at the cDNA level, p.Lys339Thr (K339T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). Using alternate nomenclature, this variant has been previously published as BRCA1 1135A>C. This variant was observed in at least one patient of Caribbean ancestry with breast cancer and was classified as a variant of unknown signficance in the publication (Hansen 2011). BRCA1 Lys339Thr 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 Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Lys339Thr occurs at a position that is not conserved and is located within the SWI/SNF binding region (Narod 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Lys339Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000472230 SCV000549314 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-12 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 339 of the BRCA1 protein (p.Lys339Thr). 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 been reported in an individual affected with breast cancer (PMID: 21318380). ClinVar contains an entry for this variant (Variation ID: 141428). 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.
Integrated Genetics/Laboratory Corporation of America RCV000587998 SCV000698827 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1016A>C (p.Lys339Thr) variant causes a missense change involving a non-conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, ESP, or publication controls). A publication cites the variant in a HBOC family, however, cosegregation and co-occurrence data was not provided. Multiple clinical diagnostic laboratories classify the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Color RCV000129938 SCV000909390 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-07 criteria provided, single submitter clinical testing

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