ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5504G>A (p.Arg1835Gln)

gnomAD frequency: 0.00001  dbSNP: rs273902776
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049023 SCV000077036 likely benign Hereditary breast ovarian cancer syndrome 2024-01-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130437 SCV000185301 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-20 criteria provided, single submitter clinical testing The p.R1835Q variant (also known as c.5504G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5504. The arginine at codon 1835 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in individuals from high-risk breast/ovarian cancer families from diverse ethnic backgrounds (Zidan J et al. Breast Cancer Res. Treat. 2017 Dec;166:881-885; Liang Y et al. Med. Sci. Monit. 2018 Apr;24:2465-2475; Bhaskaran SP et al. Int. J. Cancer. 2019 Aug;145:962-973; Purnomosari D et al. Breast Cancer Res. Treat. 2007 Dec;106:297-304; Thirthagiri E et al. Breast Cancer Res. 2008 Jul;10:R59), but also in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). This alteration was identified in a male patient with stomach cancer at age 48, and a functional comparison showed that this alteration displayed less than 70% homology-directed repair (HDR) function in comparison to wild type BRCA1 (Lu C et al. Nat Commun. 2015 Dec;6:10086). In a high throughput genome editing haploid cell survival assay, this nucleotide substitution had intermediate activity (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, two different transactivation assays demonstrated that this alteration does not significantly disrupt transactivation activity (Langerud J et al. Hum. Genomics. 2018 11;12:51; Fernández-Lopez JC et al. Hum. Genomics. 2019 01;13:3). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University RCV000240743 SCV000265893 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
GeneDx RCV000588102 SCV000566085 uncertain significance not provided 2018-12-20 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5504G>A at the cDNA level, p.Arg1835Gln (R1835Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). Using alternate nomenclature, this variant has been previously published as BRCA1 5623G>A. This variant was observed in individuals with personal and/or family histories of breast and/or ovarian cancer, as well as in at least one individual with gastric cancer (Purnomosari 2007, Thirthagiri 2008, Cunningham 2014, Lu 2015). Functional assays demonstrated that this variant displayed partial or intermediate deficiency in homology-directed repair activity, but retained normal transactivation function comparable to wild-type (Lu 2015, Woods 2016, Langerud 2018, Findlay 2018). BRCA1 Arg1835Gln was also identified in 1/46 healthy African-European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRCA1 Arg1835Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain as well as a region known to interact with multiple proteins (Paul 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Arg1835Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000130437 SCV000683328 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-30 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 1835 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in a homology-directed DNA repair assay (PMID: 26689913) and in a haploid cell proliferation assay (PMID: 30209399) and show enhanced transactivation activity (PMID: 28781887, 30458859). This variant has been reported in individuals affected with breast cancer (PMID: 17972177, 27257965, 35402282), ovarian cancer (PMID: 18627636, 24504028) and pancreatic cancer (PMID: 32980694 ). This variant has also been observed in a healthy control individual (PMID: 27403073). This variant has been identified in 9/282720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120265 SCV000699268 uncertain significance not specified 2022-09-06 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5504G>A (p.Arg1835Gln) results in a conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251424 control chromosomes.c.5504G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer from diverse ethnic populations without strong evidence for causality (eg. Purnomosari_2007, Thirthagiri_2008, Cunningham_2014, Zhong_2016, Zidan_2017, etc). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Functional studies demonstrated that the variant protein displayed partial or intermediate deficiency in homology-directed repair (HDR) activity with a preserved transactivation function (Findlay_2018, Lu_2015, Woods_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five classified the variant as VUS while one classified as likley benign. Based on the evidence outlined above, the variant was classified as VUS.
Counsyl RCV000112685 SCV000786203 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2018-03-16 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000120265 SCV002760916 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000112685 SCV004212751 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2023-09-27 criteria provided, single submitter clinical testing
ITMI RCV000120265 SCV000084417 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000112685 SCV000145553 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2010-09-18 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112685 SCV000297622 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2009-07-06 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000120265 SCV000587515 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Brotman Baty Institute, University of Washington RCV000112685 SCV001237593 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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