ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln) (rs41293459)

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Total submissions: 28
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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) RCV000031217 SCV001156534 pathogenic Breast-ovarian cancer, familial 1 2017-05-10 reviewed by expert panel curation This variant has been shown to impact function (PMID:18036263, 23867111, 30257991, 30765603, 11157798). A genetic study (PMID:22889855) reported it to be associated with reduced risk compared to another pathogenic missense substitution variant at the same residue (BRCA1 c.5095C>T p.(Arg1699Trp)). A subsequent larger genetic study including 129 families (PMID:28490613) reported HRs of 2.83 for breast cancer and 5.83 for ovarian cancer risk, and estimated the cumulative risk to age 70 to be 20% for breast cancer and 6% for ovarian cancer. This variant is considered pathogenic with reduced penetrance relative to the average BRCA1 truncating pathogenic variant. Management recommendations for this specific variant were published in 2017 (PMID:28490613). In line with a recent publication that provides guidance on reporting for reduced penetrance variants in cancer susceptibility genes (PMID:30962250), clinical management recommendations should consider knowledge of personal and family history of disease, and other known genetic and environmental risk factors, that together can strongly influence absolute risk for an individual.
Invitae RCV000195350 SCV000076803 pathogenic Hereditary breast and ovarian cancer syndrome 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1699 of the BRCA1 protein (p.Arg1699Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs41293459, ExAC 0.005%). This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 11504767, 12827452, 16683254, 20455026, 24504028, 24728189, 25452441, 28490613). In a large family cohort study, including 67 families in which the probands carried the Arg1699Gln change, this variant was shown to segregate with breast and ovarian cancer (PMID: 22889855). This variant is also known as 5215G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37636). This missense change affects the highly conserved arginine 1699 residue within the BRCT-N domain (PMID: 22843421, 11157798). While the results are somewhat conflicting among the different reports, experimental studies have shown that this missense change can disrupt several functional activities of the BRCA1 protein, including transactivation (PMID: 18036263, 17308087, 11157798), phosphopeptide binding (PMID: 21473589, 15133503, 15133502), and nuclear foci formation (PMID: 18036263). However, this variant generally exhibits reduced or intermediate BRCA1 protein function. Modified segregation analysis of 129 families carrying Arg1699Gln has shown that this variant confers intermediate risk for breast and ovarian cancer (PMID: 28490613). The risk of breast cancer by age 70 years is 20% when compared to 8% risk for women in the general population, versus 65% risk for carriers of an average pathogenic BRCA1 variant. The risk of ovarian cancer by age 70 years is 6% when compared to 1% risk for women in the general population, versus 39% risk for carriers of an average pathogenic BRCA1 variant. In summary, this variant is reported to cause an increased risk for breast and ovarian cancer. However, since this variant is associated with a lower risk than other pathogenic alleles in the BRCA1 gene, it has been classified as Pathogenic (low penetrance).
Counsyl RCV000031217 SCV000153998 likely pathogenic Breast-ovarian cancer, familial 1 2014-01-02 criteria provided, single submitter literature only
Ambry Genetics RCV000131564 SCV000186568 pathogenic Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing The p.R1699Q moderate risk mutation (also known as c.5096G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5096. The arginine at codon 1699 is replaced by glutamine, an amino acid with highly similar properties. In one functional study, the p.R1699Q alteration was shown to destabilize the BRCT domain of the BRCA1 protein and demonstrated reduced, but not abolished, BRCA1 activity (Lovelock PK et al. Breast Cancer Res. 2007;9:R82). In another functional study analyzing protein expression levels in transfected mouse embryonic stem cells, the p.R1699Q alteration showed an intermediate effect in a cisplatin sensitivity assay and a deleterious effect in a PARP inhibitor assay. This alteration also showed an intermediate level of homologous repair activity compared to wild-type. Based on these findings the authors noted that the p.R1699Q alteration would likely lead to an intermediate risk for HBOC (Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55). In a study comparing phenotype and segregation data from 68 p.R1699Q families to 34 pathogenic BRCA1 p.R1699W kindreds and 243 BRCA1 mutation-free families, results strongly supported p.R1699Q as an intermediate risk allele, conferring an estimated 24% (95% CI: 10-40%) risk of female breast or ovarian cancer by age 70 (Spurdle AB et al. J. Med. Genet. 2012 Aug;49:525-32). These risks were further supported by the ENIGMA consortium which calculated a 20% and 6% increased risk of breast and ovarian cancer, respectively, by age 70 (Moghadasi S et al. J. Med. Genet. 2018 Jan;55:15-20). Of note, this alteration is also designated as 5215G>A in published literature. Based on the available evidence, this alteration is classified as a moderate risk mutation that may not be associated with classic HBOC, but rather leads to increased risk of developing a BRCA1-related cancer. Clinical correlation is advised.
GeneDx RCV000048790 SCV000210198 pathogenic not provided 2020-03-17 criteria provided, single submitter clinical testing Multifactorial studies suggest this variant is associated with breast and ovarian cancer; however, these risks appear to be lower than typical BRCA1 pathogenic variants in multiple studies (Chenevix-Trench 2006, Lindor 2012, Spurdle 2012, Moghadasi 2017, Shimelis 2017); The ENIGMA consortium has proposed modified variant-specific breast and ovarian cancer management recommendations (Moghadasi 2017); Published functional studies are conflicting with regards to transcriptional activation, phosphopeptide binding activity, and homology-directed repair activity (Williams 2003, Lovelock 2007, Lee 2010, Woods 2016, Langerud 2018, Petitalot 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5215G>A; This variant is associated with the following publications: (PMID: 25639900, 25980754, 24675953, 25652403, 24695549, 24845084, 25556971, 25085752, 15235020, 16489001, 12827452, 16280041, 15172985, 15133503, 20378548, 22505045, 11157798, 25452441, 28400480, 29192238, 28888541, 11504767, 12237282, 22889855, 25782689, 24323938, 18036263, 21990134, 21447777, 21702907, 23231788, 23867111, 20455026, 21473589, 15290653, 19563646, 24504028, 17305420, 26777316, 19200354, 15133502, 16528612, 14534301, 26350514, 26727311, 27495310, 27099641, 26987529, 27741520, 28283652, 28398198, 28758972, 29346284, 22843421, 24728189, 28866612, 16683254, 29486991, 30458859, 30287823, 30078507, 30765603, 30612635, 30257991, 28781887, 20516115, 28490613, 12237281, 14615451, 14966099, 18042939, 22516946, 22811390, 25348405, 31347298, 31447099, 31263571, 32123317)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000195350 SCV000605739 pathogenic Hereditary breast and ovarian cancer syndrome 2019-08-07 criteria provided, single submitter clinical testing The p.Arg1699Gln variant in BRCA1 has been reported in >60 individuals with BRCA1-associated cancers and segregated with disease in multiple relatives from 30 families (Spurdle 2012, Shimelis 2017, Moghadasi 2018). This variant has been described as having reduced penetrance compared to other disease-causing variants: up to 24% risk of BRCA1-related cancer by age 70 (95% CI, 10% to 40%) for Arg1699Gln carriers vs. 58% (95% CI, 7% to 72%) for Arg1699Trp carriers vs. 4.6% risk for women in the general population (Spurdle 2012, Moghadasi 2018). It has been identified in 6/113618 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). While some studies have demonstrated impaired in vitro protein activity, others report that the variant performed similar to wild-type (Williams 2003, Lovelock 2007, Chang 2011). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as a low-penetrant pathogenic variant for autosomal dominant HBOC. ACMG/AMP criteria applied: PS4, PP1_Strong, PM5, PM2_Supporting, PP3, PS3_Supporting.
Color Health, Inc RCV000131564 SCV000683252 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-02 criteria provided, single submitter clinical testing
GeneKor MSA RCV000048790 SCV000693499 likely pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This is a single base pair change replacing arginine by glutamine at amino acid position 1699 of the BRCA1 protein. This position is highly conserved among species and there is a small physiochemical difference between arginine and glutamine (Grantham Score 43). This missense change affects the highly conserved arginine 1699 residue within the BRCT-N domain (PMID: 22843421, 11157798).This variant is present in population databases (rs41293459, <0.01%). This variant is also known as 5215G>A in the literature and it has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 11504767, 12827452, 16683254, 24728189). The mutation database Clinvar contains entries for this variant (Variation ID: 37636). Experimental studies have shown that this missense change can disrupt several functional activities of the BRCA1 protein, including transactivation (PMID: 18036263, 17308087, 11157798), phosphopeptide binding (PMID: 21473589, 15133503, 15133502), and nuclear foci formation (PMID: 18036263). However, this variant generally exhibits reduced or intermediate BRCA1 protein function. Modified segregation analysis of 30 families carrying the Arg1699Gln variant has shown that it has reduced penetrance compared with the average pathogenic, truncating BRCA1 variant. In addition, algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the BRCA1 protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000195350 SCV000699200 pathogenic Hereditary breast and ovarian cancer syndrome 2021-05-27 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5096G>A (p.Arg1699Gln) involves the alteration of a conserved nucleotide that results in a conservative amino acid change located in the first BRCT domain (IPR001357) that is involved in interactions with phosphorylated partner proteins (Petitalot 2018) and also, functions as a transcriptional activation domain (Langerud 2018). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 252122 control chromosomes (gnomAD and publications). c.5096G>A has been reported in the literature in multiple individuals/families affected with Hereditary Breast and Ovarian Cancer, and was also noted to cosegregate with the disease (Ricevuto 2001), though, in one family the variant was absent in an affected individual (Gomez Garcia 2009). Although the variant of interest was found to co-occur with another potentially pathogenic BRCA2 variant, c.631+4A>G, within a HBOC family, the authors indicated that both variants contributed to the family phenotype (Steffensen 2010). Co-occurrences with other pathogenic variant(s) have also been reported elsewhere (BRCA2 c.9026_9030delATCAT, p.Tyr3009fsX7 in the UMD database). One study reported the variant in compound heterozygosity with a known BRCA1 pathogenic variant (p.Cys61Gly) in a woman with breast cancer who showed mild Fanconi anemia (FA)-like features, with the authors concluding that the comparatively mild FA-like clinical phenotype presented was most likely due to incomplete impairment of BRCA1 function by the p.Arg1699Gln risk allele (Keupp_2019). Case-control studies concluded that the variant confers lower breast and ovarian cancer risk than a typical BRCA1 pathogenic variant (Spurdle 2012, Shimelis 2017, Moghadasi 2018), the cumulative risk of breast and ovarian cancer by age 70 years being 20% and 6%, respectively; the authors refer to the variant as an intermediate risk variant conferring risks lower than that of the average pathogenic variant (ENIGMA consortium, Moghadasi 2018). Multiple independent functional studies reporting this variant have demonstrated: 1. proper or reduced BRCT domain folding, 2. loss of phosphopeptide binding, 3. decreased or intermediate transcriptional activity of the mutant BRCA1 constructs expressed in mammalian cell lines, and 4. defective homology-directed DNA repair (HDR) capacity and nuclear foci formation in mammalian cells, but preserved wild-type centrosome amplification function (Vallon-Christersson 2001, Williams 2003, Williams 2004, Carvalho 2007, Lovelock 2007, Rowling 2010, Lee 2010, Petitalot 2018, Langerud 2018). Although it is not clear how all the results and conclusions drawn from these in-vitro studies are applicable to the mechanism and presentation of disease, the convergence of results obtained from multiple independent functional assays are supportive of a hypomorphic and damaging effect of this variant on the BRCA1 gene product. Eighteen ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000195350 SCV000839217 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000031217 SCV000839901 likely pathogenic Breast-ovarian cancer, familial 1 2017-06-02 criteria provided, single submitter clinical testing The c.5096G>A (p.Arg1699Gln) variant has been reported in multiple patients with breast and/or ovarian cancer [PMID 12827452, 24504028, 25782689]. Several functional in vitro assays showed ambiguous results: the p.Arg1699Gln showed intermediate deleterious effects but not to the extend of a well -characterized pathogenic variant [PMID 22889855, 23867111, 21473589]. Additionally, this variant showed a reduced penetrance in a study [PMID 22889855] and the risk for breast or ovarian cancer was reduced to 24 % by age 70. Additional changes affecting the same amino acid position (p.Arg1699Arg, p.Arg1699Leu, p.Arg1699Trp) have also been reported in patients with breast and/or ovarian cancer. This variant was reported in 3 heterozygous individuals in ExAC (http://exac.broadinstitute.org/variant/17-41215947-C-T). This variant is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Arg1699Gln change to be deleterious. This variant thus classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048790 SCV000887711 pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing
Mendelics RCV000031217 SCV001140488 pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000048790 SCV001247343 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000048790 SCV001449650 likely pathogenic not provided 2016-05-25 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659881 SCV001878729 uncertain significance Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
OMIM RCV000031217 SCV000043748 pathogenic Breast-ovarian cancer, familial 1 2001-02-15 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000031217 SCV000053817 likely pathogenic Breast-ovarian cancer, familial 1 2013-07-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031217 SCV000145310 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Division of Human Genetics,Medical University Innsbruck RCV000031217 SCV000212005 likely pathogenic Breast-ovarian cancer, familial 1 2015-02-11 no assertion criteria provided clinical testing
Department of Medical Genetics, University Hospital of North Norway RCV000031217 SCV000301436 likely pathogenic Breast-ovarian cancer, familial 1 2016-05-01 no assertion criteria provided clinical testing
GeneReviews RCV000031217 SCV000484957 pathogenic Breast-ovarian cancer, familial 1 2016-12-15 no assertion criteria provided literature only
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000195350 SCV000587462 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 RCV000735446 SCV000863582 uncertain significance Breast and/or ovarian cancer 2013-08-26 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785422 SCV000923994 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000048790 SCV001743035 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000048790 SCV001954720 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000048790 SCV001975365 pathogenic not provided no assertion criteria provided clinical testing

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