ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.140G>T (p.Cys47Phe) (rs80357150)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centro de Genética y Biología Molecular, Universidad de San Martín de Porres RCV000111876 SCV000282660 likely pathogenic Breast-ovarian cancer, familial 1 2016-06-06 criteria provided, single submitter clinical testing No present in population-based study (100 controls)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000111876 SCV000296426 pathogenic Breast-ovarian cancer, familial 1 2016-02-09 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000111876 SCV000325065 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000111876 SCV000564344 likely pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000775193 SCV000909419 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-13 criteria provided, single submitter clinical testing This missense variant replaces cysteine with phenylalanine at codon 47 in the RING and BARD1 binding domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional RNA study has shown that this variant had no effect on splicing (PMID: 22505045). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399) and partially abolished BRCA1 activity in the small colony phenotype (SCP) assay in yeast (PMID: 21922593). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12698193, 15887246, 27495310, 28944232). A different variant affecting the same codon, c.140G>A (p.Cys47Tyr), is considered to be disease-causing (ClinVar variation ID: 54246), suggesting that this position is functionally and clinically important. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781002 SCV000918747 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-12-01 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.140G>T (p.Cys47Phe) variant involves the alteration of a conserved nucleotide located in the Zinc finger, RING-type domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 245240 control chromosomes (gnomAD and Buleje_2017). This variant has been reported in multiple affected individuals/families with HBOC (Scottish-Northern Irish Consortium_2003, Buleje_2017). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Functional assays provide conflicting results with some showing increased number of cells per colony (more than double) and higher cell concentration (approximately 50%) associated with this variant, while others showing results comparable to WT (Millot_2012, Houdayer_2012, and Thouvenot_2016). One study showed a predicted HDR assay (based on E3 ubiquitin ligase activity and binding to the BARD1 RING domain) of approximately 20% of WT (Starita_2015). Variant involving the same codon, such as C47G and C47Y have been reported in affected individuals and classified as likely pathogenic and VUS-possibly pathogenic by our lab, suggesting the functional importance of this codon. Taken together, this variant is currently classified as likely pathogenic until more information becomes available.
Ambry Genetics RCV000775193 SCV001171713 likely pathogenic Hereditary cancer-predisposing syndrome 2017-02-20 criteria provided, single submitter clinical testing The p.C47F variant (also known as c.140G>T), located in coding exon 3 of the BRCA1 gene, results from a G to T substitution at nucleotide position 140. The cysteine at codon 47 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been identified in multiple breast and/or ovarian cancer families (Scottish/N.Irish consortium. Br. J. Cancer, 2003 Apr;88:1256-62; Jarhelle E et al. Fam. Cancer, 2017 Jan;16:1-16; <span style="font-family:arial,sans-serif; font-size:10pt">Bonadona V et al. <span style="font-family:arial,sans-serif">Genes Chromosomes Cancer, 2005 Aug;43:404-13). This variant affects an amino acid that is responsible for coordinating the binding of a zinc molecule within the BRCA1 RING finger motif and most substitutions here, including to phenylalanine, are structurally and functionally deleterious (Brzovic PS et al Nat Struct Biol. 2001; 8(10): 833-7; Millot GA et al. Hum. Mutat., 2011 Dec;32:1470-80; Thouvenot P et al. PLoS Genet., 2016 06;12:e1006096; Starita LM et al. Genetics, 2015 Jun;200:413-22; Findlay GM et al. Nature, 2018 Sep;). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000781002 SCV001574882 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 47 of the BRCA1 protein (p.Cys47Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12698193, 29339979, 29446198, 27495310, 15887246, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 54247). This variant has been reported to affect BRCA1 protein function (PMID: 30209399, 25823446, 21922593). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111876 SCV000144455 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Medical Genetics, University Hospital of North Norway RCV000111876 SCV000301425 likely pathogenic Breast-ovarian cancer, familial 1 2016-05-01 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000111876 SCV001237965 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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