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

dbSNP: rs80357150

Total submissions: 13

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, susceptibility to, 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, susceptibility to, 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, susceptibility to, 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, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775193	SCV000909419	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-07	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). 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, 34072659), and has been identified in 6 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.140G>T (p.Cys47Phe) results in a non-conservative amino acid change located in the RING-type Zinc finger domain (IPR001841) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249856 control chromosomes in gnomAD. c.140G>T has been reported in multiple individuals/families affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Scottish-Northern Irish Consortium_2003, Buleje_2017, Zhu_ 2022, Solano_ 2021, Rebbeck_2018). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity based on E3 ubiquitin ligase activity and binding to the BARD1 RING domain (Starita_2015). Additionally, at least one variant at the Arg148 residue has been reported as associated with disease (p.Arg148His, common DV), suggesting that this codon is functionally important. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID:15887246, 28944232, 32341426, 22505045, 27495310, 21922593, 12698193, 34072659, 25823446, 27272900, 29446198, 34403063). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, including 2 Pathogenic and 6 likely pathogenic classifications. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000775193	SCV001171713	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-26	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 alteration has been identified in multiple breast and/or ovarian cancer families (Scottish/N.Irish consortium. Br. J. Cancer, 2003 Apr;88:1256-62; Bonadona V et al. Genes Chromosomes Cancer, 2005 Aug;43:404-13; Jarhelle E et al. Fam. Cancer, 2017 Jan;16:1-16; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; De Talhouet S et al. Sci Rep, 2020 04;10:7073). 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 deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000781002	SCV001574882	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-24	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 21922593, 25823446, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 54247). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12698193, 15887246, 27495310, 29339979, 29446198, 32341426; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 47 of the BRCA1 protein (p.Cys47Phe).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493427	SCV004242855	likely pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111876	SCV000144455	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 1	2016-05-01	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111876	SCV001237965	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Center for Precision Medicine, Meizhou People's Hospital	RCV002250525	SCV002520917	likely pathogenic	Familial cancer of breast		no assertion criteria provided	literature only