ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.131G>T (p.Cys44Phe) (rs80357446)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077487 SCV001161535 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999964
Ambry Genetics RCV000166901 SCV000217719 pathogenic Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing The p.C44F pathogenic mutation (also known as c.131G>T), located in coding exon 2 of the BRCA1 gene, results from a G to T substitution at nucleotide position 131. The cysteine at codon 44 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This mutation occurs in the functionally important RING finger domain (Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507). Based on internal structural assessment, this alteration is predicted to disrupt formation of zinc binding site 1 and overall folding of the BRCA1 protein. This is consistent with Brzovic PS et al (2010), who showed that experimentally altering ligands at this residue yields BRCA1 RING domains that fail to fold properly (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8:833-7). Multiple functional studies have shown that this alteration is deleterious including a centrosome amplification assay, a homology directed repair assay, a single stranded annealing assay and a high throughput cell survival assay (Kais Z et al. Oncogene. 2012 Feb;31:799-804; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Findlay GM et al. Nature, 2018 Sep;). This mutation has been identified in multiple breast and/or ovarian cancer families in the literature and (Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63; Jalkh N et al. Hered Cancer Clin Pract. 2012 Jun;10:7; George J et al. Clin. Cancer. Res. 2013 Jul;19:3474-84; Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141:750-756). In addition, two other alterations at the same codon, p.C44Y and p.C44S, have been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Michigan Medical Genetics Laboratories,University of Michigan RCV000077487 SCV000267678 pathogenic Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077487 SCV000296342 pathogenic Breast-ovarian cancer, familial 1 2015-05-14 criteria provided, single submitter clinical testing
GeneKor MSA RCV000434130 SCV000296760 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variant is a single amino acid change from Cysteine to Phenylalanine at amino acid residue 44 of the BRCA1 protein. The Cysteine residue is highly conserved among species and is located in a functional domain of the protein and a region known to interact with multiple proteins. There is a large physiochemical difference between Cysteine acid and Phenylalanine (Grantham Score 205). To our knowledge, this variant is not present in population databases (rs80357446). This variant is also known as c.250G>T in the literature and it was shown to disrupt normal protein function by a yeast two-hybrid E3 Ub-ligase activity assay, a homology directed recombination assay, a BARD1 binding assay and a centrosome amplification assay (PMID: 20103620, 21725363). In addition, several individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer syndrome were found to carry this variant (PMID: 22713736). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein. The mutation database Clinvar contains entries for this variant (Variation ID: 54200).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077487 SCV000325012 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000434130 SCV000512277 pathogenic not provided 2018-04-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.131G>T at the cDNA level, p.Cys44Phe (C44F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGC>TTC). This variant, also reported as 250G>T using alternate nomenclature, has been identified in several individuals with personal and/or family histories consistent with Hereditary Breast and Ovarian Cancer syndrome (John 2007, Hall 2009, Jalkh 2012, Lolas Hamameh 2017). Functional analyses have found BRCA1 Cys44Phe to disrupt homology-directed repair and BARD1 binding, as well as result in loss of E3 ubiquitin ligase activity and centrosome amplification (Morris 2006, Ransburgh 2010, Kais 2012, Starita 2015). BRCA1 Cys44Phe was not observed in large population cohorts (Lek 2016). This variant is located in the BRD7 and BARD1 binding domains and at a ubiquitination site within the RING finger domain (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 the current evidence, we consider this variant to be pathogenic.
Counsyl RCV000077487 SCV000677632 pathogenic Breast-ovarian cancer, familial 1 2017-02-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166901 SCV000682947 pathogenic Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000434130 SCV000888841 pathogenic not provided 2019-09-11 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Located in potentially critical domain of the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Appears to be associated with disease.
Fulgent Genetics,Fulgent Genetics RCV000763011 SCV000893456 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496386 SCV000918696 pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.131G>T (p.Cys44Phe) results in a non-conservative amino acid change located in the RING binding domain 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 245760 control chromosomes (gnomAD). The variant, c.131G>T, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Alsop_2012, Jalkh_2012, El Saghir_2015, Christie_2017, etc). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies found that the variant significantly impacts proper BRCA1 protein function (Kais_2012, Morris_2006,Ransburgh_2010, Towler_2013, and Thouvenot_2016). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000434130 SCV001450125 pathogenic not provided 2014-11-18 criteria provided, single submitter clinical testing
Invitae RCV000496386 SCV001591919 pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-28 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 44 of the BRCA1 protein (p.Cys44Phe). 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 (rs80357446, ExAC no frequency). This variant has been reported in individuals affected with breast and or ovarian cancer (PMID: 23633455, 18159056, 25777348, 16267036). This variant is also known as 250G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54200). This variant affects the highly conserved Cys44 Zn-binding residue of the N-terminal BRCA1 RING domain (PMID: 12732733, 22843421). Experimental studies have shown that this missense change disrupts several BRCA1 protein functions, including single-strand annealing and homology directed repair, regulation of centrosome duplication, BARD1 binding and ubiquitin ligase activity (PMID: 20103620, 16403807, 23161852, 21725363, 27272900). Different missense substitutions at this codon, including p.Cys44Tyr, have been reported in affected individuals and determined to be pathogenic (PMID: 19543972, 27083775, 21922593, 25823446). This suggests that the cysteine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV001660055 SCV001878106 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077487 SCV000109285 pathogenic Breast-ovarian cancer, familial 1 2012-08-07 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077487 SCV000144404 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496386 SCV000587017 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735465 SCV000863602 pathogenic Breast and/or ovarian cancer 2011-11-10 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077487 SCV001242872 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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