ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.154C>T (p.Leu52Phe) (rs80357084)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085660 SCV000075532 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000164750 SCV000215424 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-09 criteria provided, single submitter clinical testing The p.L52F variant (also known as c.154C>T<span style="background-color:initial">), located in coding exon 3 of the BRCA1<span style="background-color:initial"> gene, results from a C to T substitution at nucleotide position 154. The leucine at codon 52 is replaced by phenylalanine, an amino acid with highly similar properties.<span style="background-color:initial; color:rgb(0, 0, 0)"> This variant has been detected in numerous Japanese and Korean cohorts of selected and unselected breast and/or ovarian cancer patients as well as in some control populations (Han SH et al. Clin. Genet. 2006 Dec;70:496-501; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Arai M et al. J. Hum. Genet., 2018 Apr;63:447-457; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Li JY et al. Int. J. Cancer, 2019 Jan;144:281-289).<span style="background-color:initial"> This alteration has also been reported in a cohort of individuals with epithelial ovarian cancer (Eoh KJ et al. Cancer Res Treat, 2017 Sep;). <span style="background-color:initial">Functional studies indicate that the p.L52F variant, which is located in the BRCA1 RING domain, does not significantly affect the ability of the BRCA1 protein to repair double stranded breaks by homology-directed recombination (HDR) or single strand annealing (SSA) (Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; <span style="background-color:initial">Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45). Although studies agree that this alteration is able to bind to BARD1, they do not agree on the ability of this variant to conduct subsequent E3 ubiquitin ligase functions and the clinical contribution of impaired ubiquitin ligase activity remains unclear (Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100:5646-51; Morris JR et al. Hum. Mol. Genet. 2006 Feb;15:599-606; Starita LM et al. Genetics. 2015 Jun;200:413-22). <span style="background-color:initial">Another study indicates that this variant has an intermediate effect on centrosome duplication but has no effect on centriole pairing (Kais Z et al. Oncogene. 2012 Feb 9;31:799-804). Finally, this alteration was found to function normally by an assay measuring cellular fitness in a haploid human cell line whose survival was dependant on intact BRCA1 function (Findlay GM et al. Nature, 2018 10;562:217-222). <span style="background-color:initial">This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction by BayesDel for this alteration is inconclusive.<span style="background-color:initial"> Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
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
Color Health, Inc RCV000164750 SCV000682971 likely benign Hereditary cancer-predisposing syndrome 2020-11-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000236664 SCV000698873 benign not specified 2021-02-21 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 variant allele was found at a frequency of 0.00065 in 299432 control chromosomes, predominantly at a frequency of 0.0014 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome 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 predominantly from East Asian cohorts of individuals affected with Breast and/or Ovarian Cancer (example, Sugano_2008, Han_2006, Jang_2012, Kim_2006, Judkins_2005, Eoh_2017, Yoon_2016, Park_2017, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.5645C>A , p.Ser1882X), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on protein expression, HDR activity, or BARD1 binding (example, Yoon_2017, Starita_2015, Ransburgh_2010, Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of any evidence supporting an actionable outcome spanning at-least 12 years of cross sectional review, supported by multiple reports of a neutral functional impact and at-least one co-occurrence as outlined above, the variant was classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000031002 SCV001287535 uncertain significance Breast-ovarian cancer, familial 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Breast Center,Key Laboratory of Carcinogenesis and Translational Research RCV001085660 SCV001430328 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-05-01 criteria provided, single submitter clinical testing
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031002 SCV000591244 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The p.Leu52Phe variant has been identified in 11 out of 3896 proband chromosomes (frequency 0.003) from individuals with breast and ovarian cancers, and was not identified in 668 control chromosomes (Kim 2006, Han 2006, Sugano 2008 ), increasing the likelihood this variant may have clinical significance. However, it should be noted that this individual was indicated as Asian, and our lab has sequenced the BRCA1 gene in a limited number of individuals from this background such that the full spectrum of benign variation may not yet been defined for this gene in this population and increasing the possibility that this may be a benign variant. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs80357084) with no frequency information available, and so the frequency of this variant in the general population is not known. The p.Leu52 is conserved in mammals and other species and in-silico or computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that this variant may impact protein function, however this is not predictive enough to assume pathogenicity. Several in vitro studies suggested modest to no effect regarding the role of this variant in centrosome duplication, binding to BARD1, and ubiquitination activity (Brzovic 2003, Morris 2006, Ransburgh 2010, Sarkar 2008, Katoh 2005, Kais 2012, Atipairin 2011). In summary, based on current information presented above, we cannot rule out the possibility that this variant may have clinical significance, but this variant is classified as VUS.
Brotman Baty Institute,University of Washington RCV000031002 SCV001241594 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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