ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4454C>T (p.Thr1485Ile) (rs80356870)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048563 SCV000076576 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-02-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1485 of the BRCA1 protein (p.Thr1485Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 24321281). ClinVar contains an entry for this variant (Variation ID: 55203). The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. Furthermore, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
Ambry Genetics RCV000167166 SCV000217999 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000780980 SCV000918703 uncertain significance not specified 2017-10-05 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4454C>T (p.Thr1485Ile) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 246062 control chromosomes (gnomAD). In literature, this variant has been reported in one ovarian cancer patient without strong evidence for or against pathogenicity (Li_2013). In vitro functional analysis showed that this variant leads to increased transcriptional activity due to which the authors classified it as likely not pathogenic (Woods_2016). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is currently classified as Variant of Unknown Significance.
Sharing Clinical Reports Project (SCRP) RCV000077573 SCV000109376 uncertain significance Breast-ovarian cancer, familial 1 2009-12-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077573 SCV000145089 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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