ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4427A>C (p.Lys1476Thr) (rs750437234)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586593 SCV000699150 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4427A>C (p.Lys1476Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 1/121378 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Homology-directed repair (HDR) assays showed the variant does not affect HDR activity, though appropriate controls were not available for evaluation (Lu_BRCA_Nature Comms_2015). Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).
Invitae RCV000818385 SCV000958995 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 1476 of the BRCA1 protein (p.Lys1476Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs750437234, ExAC 0.001%). This variant has been observed in an individual affected with prostate cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 496384). Experimental studies investigating homology-directed repair (HDR) have shown that this missense change functions similar to wild type protein (PMID: 26689913). 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.

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