ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5072C>A (p.Thr1691Lys) (rs80357034)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574915 SCV000660999 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Structural Evidence,Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA1) RCV000031208 SCV000145285 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Color RCV000574915 SCV000908995 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-15 criteria provided, single submitter clinical testing
GeneDx RCV000485950 SCV000568400 likely pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5072C>A at the cDNA level, p.Thr1691Lys (T1691K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). Using alternate nomenclature, this variant has been previously published as BRCA1 5191C>A. This variant was observed in several women with breast and/or ovarian cancer (Lin 2011, Kuo 2012, Wong 2015, Ng 2016, Chirasophon 2017). In addition, multiple functional studies have demonstrated this variant to have a severe impact on transactivation, protease sensitivity, binding activity and sensitivity, nuclear spot formation, decreased nuclear localization and absence of growth inhibition (Lee 2010, Kuo 2012, Thouvenot 2016, Woods 2016). BRCA1 Thr1691Lys was not observed in large population cohorts (Lek 2016). This variant is located in the BRCT1 domain and within a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider BRCA1 Thr1691Lys to be a likely pathogenic variant.
Invitae RCV000048760 SCV000076773 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 1691 of the BRCA1 protein (p.Thr1691Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 22277901, 26757417). This variant is also known as 5191C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37627). Experimental studies have shown that this missense change has a severe effect on BRCA1 protein folding, binding ability and transcriptional activation (PMID: 20516115, 22277901). A different missense substitution at this codon (p.Thr1691Ile) segregated with disease in a family affected with breast and pancreatic cancer and has been determined to be likely pathogenic (Invitae database). This suggests that the threonine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be likely pathogenic. For these reasons, this variant has been classified as Likely Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031208 SCV000053808 uncertain significance Breast-ovarian cancer, familial 1 2008-11-20 no assertion criteria provided clinical testing

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