ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.154C>T (p.Leu52Phe) (rs80357084)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047519 SCV000075532 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000164750 SCV000215424 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
GeneDx RCV000588129 SCV000293475 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.154C>T at the cDNA level, p.Leu52Phe (L52F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). Using alternate nomenclature, this variant would be defined as BRCA1 273C>T. This variant has been identified in primarily Asian individuals with a personal history of breast and/or ovarian cancer, but has also been observed in healthy controls (Han 2006, Kim 2006, Sugano 2008, Jang 2012, Hirotsu 2015, Nakamura 2015, Yoon 2016, Ryu 2017). While BRCA1 Leu52Phe was found to have BARD1 binding, homology-directed repair, and single-stranded DNA repair activity similar to wild-type (Morris 2006, Ransburgh 2010, Towler 2013, Starita 2015, Starita 2018), E3 ubiquitin ligase activity and E2 binding have been shown to be decreased (Morris 2006, Starita 2015), and Kais et al. (2012) observed an intermediate increase in centrosome amplification. However, Brzovic et al. (2003) found ubiquitin ligase activity comparable to wild-type. BRCA1 Leu52Phe was observed at an allele frequency of 0.16% (27/17,234) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the BRD7 and BARD1 binding domains and a region that undergoes ubiquitination within the RING finger domain (Wu 1996, Narod 2004, Harte 2010, Borg 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 Leu52Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000031002 SCV000487928 uncertain significance Breast-ovarian cancer, familial 1 2015-12-22 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000236664 SCV000586865 likely benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236664 SCV000591244 uncertain significance not specified 2012-04-06 criteria provided, single submitter clinical testing
Color RCV000164750 SCV000682971 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000236664 SCV000698873 likely benign not specified 2018-05-04 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.154C>T (p.Leu52Phe) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.6 fold above the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.154C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong supporting evidence. These reports do not provide unequivocal conclusions about an association of the variant with Hereditary Breast and Ovarian Cancer. Multiple publications report experimental evidence showing that the variant has no damaging effect on protein expression, HDR activity, or BARD1 binding (Yoon_2017, Starita_2015, Ransburgh_2010). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations including uncertain significance (4x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031002 SCV000053594 uncertain significance Breast-ovarian cancer, familial 1 2012-12-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031002 SCV000144495 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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