ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.189A>T (p.Leu63Phe) (rs80356956)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047628 SCV000075641 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 63 of the BRCA1 protein (p.Leu63Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with B-cell lymphoma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 54389). This variant is located in the RING domain of the BRCA1 protein (PMID: 11573085, 24489791). Experimental studies have shown that this missense change disrupts the ubiquitin ligase activity of the BRCA1/BARD1 heterodimer in vitro (PMID: 12732733, 16403807, 25723446). 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.
GeneDx RCV000590194 SCV000567773 uncertain significance not provided 2018-11-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.189A>T at the cDNA level, p.Leu63Phe (L63F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTA>TTT). Using alternate nomenclature, this variant would be defined as BRCA1 308A>T. This variant has been observed in at least one individual with breast and/or ovarian cancer and a child with B-cell acute lymphoblastic leukemia (Brzovic 2001, Zhang 2015). Additionally, BRCA1 Leu63Phe has been shown to disrupt ubiquitin ligase activity of the BRCA1/BARD1 heterodimer and to impair the ability of BRCA1 to repress ER-alpha activity compared to the wild-type controls (Brzovic 2003, Ma 2005, Morris 2006). BRCA1 Leu63Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RING finger and ubiquitination site within the RING domain and interacts with multiple proteins (Wu 1996, Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Leu63Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485649 SCV000600272 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567313 SCV000665811 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590194 SCV000698897 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.189A>T (p.Leu63Phe) variant involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a damaging outcome. This variant was found in 1/245770 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant of interest is located in the RING-finger domain of BRCA1, and cancer-predisposing mutations within the RING domain of BRCA1 have been correlated with loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity [PubMed: 11320250]. The variant of interest was found to impact ubiquitin ligase activity (Brzovic_2003). Although L63F does not affect estrogen receptor-alpha binding, it does disrupt the ability of BRCA1 to repress estrogen receptor-alpha activity; but, the in vivo significance of this partial loss of BRCA1 function and its role in cancer has not been established. Furthermore, it has been reported that some variants with defects in E3 ubiquitin ligase activity are not compromised for the ability towards homology directed repair and tumor suppression. Therefore, the biological and clinical significance of this finding remains uncertain. The variant of interest, to our knowledge, has not been reported in affected individuals presenting with BRCA1 phenotypes (HBOC, BrC, PrC, OvC, etc) via publications. Multiple clinical diagnostic laboratories/reputable databases have cited this variant with a classification of "uncertain significance." Taken together, the variant of interest has been classified as a "Variant of Uncertain Significance" until additional information becomes available.
Color RCV000567313 SCV000911511 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-21 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111972 SCV000144593 uncertain significance Breast-ovarian cancer, familial 1 1999-12-30 no assertion criteria provided clinical testing

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