ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5504G>A (p.Arg1835Gln) (rs273902776)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049023 SCV000077036 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1835 of the BRCA1 protein (p.Arg1835Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs273902776, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 17972177, 18627636, 27257965), and in control individuals (PMID: 27403073). ClinVar contains an entry for this variant (Variation ID: 55604). Experimental studies have shown that this missense change partially disrupts BRCA1 homology-directed repair activity (PMID: 26689913). However, another study showed that this variant does not impair BRCA1 transcriptional activation (PMID: 28781887). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000130437 SCV000185301 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240743 SCV000265893 uncertain significance Neoplasm of the breast 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 RCV000130437 SCV000683328 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588102 SCV000699268 uncertain significance not provided 2016-11-25 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5504G>A (p.Arg1835Gln) variant is located in the second BRCT domain causing a missense change involving a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. The variant was observed in the large, broad control population, ExAC, with an allele frequency of 3/121360 (1/40453), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in multiple affected indvidiuals via publications, although with limited information (ie, lack of co-occurrence and cosegregation data). Functional studies evaluated the efficiancy of the variant in HDR and transcriptional activation. Lu_2015 indicates the variant to have significantly less HDR efficiency then the WT suggesting a deleterious impact, while Woods_2016 indicates the variant to have slightly stronger transcriptional activity than the wild type with a classification of "not likely pathogenic." In addition, multiple clinical diagnostic laboratories, databases, and publications cite the variant as "uncertain significance." Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Counsyl RCV000112685 SCV000786203 uncertain significance Breast-ovarian cancer, familial 1 2018-03-16 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 1 2010-09-18 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112685 SCV000297622 uncertain significance Breast-ovarian cancer, familial 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

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