ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs41293459
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Total submissions: 50
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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, susceptibility to, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000195350 SCV000076803 pathogenic, low penetrance Hereditary breast ovarian cancer syndrome 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1699 of the BRCA1 protein (p.Arg1699Gln). This variant is present in population databases (rs41293459, gnomAD 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. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37636). 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. 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance 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, susceptibility to, 1 2014-01-02 criteria provided, single submitter literature only
Ambry Genetics RCV000131564 SCV000186568 pathogenic Hereditary cancer-predisposing syndrome 2024-02-22 criteria provided, single submitter clinical testing The c.5096G>A (p.R1699Q) alteration is located in exon 17 (coding exon 16) of the BRCA1 gene. This alteration results from a G to A substitution at nucleotide position 5096, causing the arginine (R) at amino acid position 1699 to be replaced by a glutamine (Q)._x000D_ _x000D_ Alteration conclusion statement: Based on the available evidence, the BRCA1 c.5096G>A (p.R1699Q) alteration is classified as pathogenic and is a moderate risk mutation that may not be associated with classic HBOC, but rather leads to increased risk of developing a BRCA1-related cancer. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (6/251262) total alleles studied. The highest observed frequency was 0.005% (6/113618) of European (non-Finnish) alleles. 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, 2012). 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, 2018). This mutation has also been detected in trans with BRCA1 c.181T>G (p.C61G) in an individual diagnosed with breast cancer at age 30 years and a mild Fanconi anemia phenotype lacking chromosome fragility (Keupp, 2019). Of note, this alteration is also designated as 5215G>A in published literature. This amino acid position is highly conserved in available vertebrate species. 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, 2007). 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, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx RCV000048790 SCV000210198 pathogenic not provided 2024-05-06 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 (PMID: 16489001, 21990134, 22889855, 28490613, 28283652); The ENIGMA consortium has proposed modified variant-specific breast and ovarian cancer management recommendations (PMID: 28490613); Published functional studies are conflicting with regards to transcriptional activation, phosphopeptide binding activity, and homology-directed repair activity (PMID: 30458859, 28781887, 30257991, 20516115, 14534301, 18036263); 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, 32980694, 32211327, 38167124, 12237282, 29922827, 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, 33309985, 32719484, 32710294, 33087888, 30787465, 34308104, 30130155, 35264596, 33804961, 34697415, 35464868, 35665744, 34663891, 35918668, 34981296, 35957908, 35534704, 34284872, 36243179, 29053726, 34887416, 33471991)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000195350 SCV000605739 pathogenic Hereditary breast 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 Diagnostics, LLC DBA Color Health RCV000131564 SCV000683252 pathogenic Hereditary cancer-predisposing syndrome 2023-03-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 1699 in the BRCT1 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). Functional studies have reported that this variant partially to fully impacts BRCA1 function in homology-directed repair and cisplatin sensitivity assays (PMID: 23867111, 28398198) and transcription activation and phosphopeptide binding assays (PMID: 11157798, 15133502, 15133503, 18036263, 20516115). This variant has been detected in over 20 individuals and families affected with breast and ovarian cancer (PMID: 11157798, 11410501, 11504767, 12827452, 24504028, 24728189, 25452441, 27495310, 28283652, 29486991, 30287823, 33471991, 35039564). This variant has been reported to be of reduced penetrance, conferring intermediate risk for breast and ovarian cancer based on case-control studies, analysis of carrier family history, and functional studies (PMID: 16489001, 22889855, 28283652, 28490613). In particular, a study of 129 families carrying this variant have shown cumulative risks for this variant by age 70 years are about 20% (95% CI 13% to 32%) for breast cancer and 6% (95% CI 3% to 25%) for ovarian cancer. These risks are lower than for high-risk BRCA1 truncating variants and higher than for the general population (PMID: 28490613). This variant has been identified in 6/251262 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 8 unaffected individuals (PMID: 33471991). A different variant affecting the same codon, p.Arg1699Trp, is considered to be disease-causing (ClinVar variation ID: 55396), suggesting that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic with reduced penetrance.
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 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000031217 SCV000839901 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 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 2023-06-08 criteria provided, single submitter clinical testing The BRCA1 c.5096G>A (p.Arg1699Gln) variant has been reported in the published literature in multiple individuals with breast or ovarian cancer (PMIDs: 35918668 (2022), 26350514 (2015), 25452441 (2015), 22034289 (2012), 20455026 (2010), 12827452 (2003), 11504767 (2001)). However, this variant is reported as being associated with reduced penetrance, relative to other BRCA1 pathogenic variants (PMIDs: 31347298 (2019), 28490613 (2017), 28283652 (2017), 26777316 (2016), 26430151 (2015), 25085762 (2014), 22889855 (2012)). In general, functional studies have shown that this variant causes a reduction in BRCA1 protein activity (PMIDs: 28781887 (2016), 23867111 (2013), 21946536 (2011), 20516115 (2010), 21473589 (2011), 17308087 (2007), 11157798 (2001)). The frequency of this variant in the general population, 0.000053 (6/113618 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as a BRCA1 pathogenic variant with reduced penetrance, relative to other BRCA1 pathogenic variants.
Mendelics RCV000031217 SCV001140488 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000048790 SCV001247343 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000048790 SCV001449650 likely pathogenic not provided 2016-05-25 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000048790 SCV002009427 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000048790 SCV002017873 pathogenic not provided 2022-10-28 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV000195350 SCV002025914 pathogenic Hereditary breast ovarian cancer syndrome 2021-11-16 criteria provided, single submitter clinical testing
DASA RCV000031217 SCV002318946 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-03-25 criteria provided, single submitter clinical testing The c.5096G>A;p.(Arg1699Gln) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37636; PMID: 28490613) -PS4. The variant is present at low allele frequencies population databases (rs41293459 – gnomAD 0.0002388%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 55396) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 22889855, 28490613) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic
Genetics Program, Instituto Nacional de Cancer RCV000195350 SCV002515224 pathogenic Hereditary breast ovarian cancer syndrome 2021-11-01 criteria provided, single submitter research
Sema4, Sema4 RCV000131564 SCV002537809 likely pathogenic Hereditary cancer-predisposing syndrome 2022-03-05 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000048790 SCV002550955 pathogenic not provided 2024-07-31 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496477 SCV002813824 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2021-11-24 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000735446 SCV003838234 likely pathogenic Breast and/or ovarian cancer 2023-04-06 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000031217 SCV004027795 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-05-02 criteria provided, single submitter clinical testing Criteria applied: PS4,PM2_SUP,PP3, PS3_SUP, PM5
Baylor Genetics RCV000031217 SCV004212746 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-03-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000048790 SCV004224805 pathogenic not provided 2023-05-03 criteria provided, single submitter clinical testing PP3, PP5, PM3_supporting, PS3, PS4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000048790 SCV004562806 likely pathogenic not provided 2023-05-09 criteria provided, single submitter clinical testing The BRCA1 c.5096G>A; p.Arg1699Gln variant (rs41293459), also known as 5215G>A, is reported in the literature in multiple individuals affected with breast or ovarian cancer (Couch 2015, Cunningham 2014, Rostagno 2003, Song 2014), but with reduced penetrance and an intermediate cancer risk compared to other pathogenic BRCA1 variants (Moghadasi 2018, Spurdle 2012). Functional analyses of the variant protein show conflicting results, with significant reductions in transcriptional activation (Lovelock 2007) and protein interactions (Coquelle 2011), but retention of an intermediate level of homologous recombination activity (Bouwman 2013), altogether suggestive of a hypomorphic and damaging effect. This variant is classified as pathogenic by an expert panel in ClinVar (Variation ID: 37636). It is only found on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.785). Additionally, another variant at this codon (c.5095C>T; p.Arg1699Trp) has been reported in individuals with breast or ovarian cancer and is considered pathogenic (Song 2014, Spurdle 2012). Based on available information, this variant is considered to be likely pathogenic with reduced penetrance and an intermediate risk for breast and ovarian cancer. References: Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov 2013 3(10):1142-55. PMID: 23867111. Coquelle N et al. Impact of BRCA1 BRCT domain missense substitutions on phosphopeptide recognition. Biochemistry 2011 50(21):4579-89. PMID: 21473589. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. PMID: 25452441. Cunningham JM et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 Feb 7;4:4026. PMID: 24504028. Lovelock P et al. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants? Breast Cancer Res 2007 9(6):R82. PMID: 18036263. Moghadasi S et al. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium. J Med Genet. 2018 Jan;55(1):15-20. PMID: 28490613. Rostagno P et al. A mutation analysis of the BRCA1 gene in 140 families from southeast France with a history of breast and/or ovarian cancer. J Hum Genet. 2003;48(7):362-6. PMID: 12827452. Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9. PMID: 24728189. Spurdle A et al. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk. J Med Genet 2012 49(8):525-32. PMID: 22889855.
All of Us Research Program, National Institutes of Health RCV000031217 SCV004817593 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 1699 in the BRCT1 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). Functional studies have reported that this variant partially to fully impacts BRCA1 function in homology-directed repair and cisplatin sensitivity assays (PMID: 23867111, 28398198) and transcription activation and phosphopeptide binding assays (PMID: 11157798, 15133502, 15133503, 18036263, 20516115). This variant has been detected in over 20 individuals and families affected with breast and ovarian cancer (PMID: 11157798, 11410501, 11504767, 12827452, 24504028, 24728189, 25452441, 27495310, 28283652, 29486991, 30287823, 33471991, 35039564). This variant has been reported to be of reduced penetrance, conferring intermediate risk for breast and ovarian cancer based on case-control studies, analysis of carrier family history, and functional studies (PMID: 16489001, 22889855, 28283652, 28490613). In particular, a study of 129 families carrying this variant have shown cumulative risks for this variant by age 70 years are about 20% (95% CI 13% to 32%) for breast cancer and 6% (95% CI 3% to 25%) for ovarian cancer. These risks are lower than for high-risk BRCA1 truncating variants and higher than for the general population (PMID: 28490613). This variant has been identified in 6/251262 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 8 unaffected individuals (PMID: 33471991). A different variant affecting the same codon, p.Arg1699Trp, is considered to be disease-causing (ClinVar variation ID: 55396), suggesting that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic with reduced penetrance.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000195350 SCV005045701 pathogenic Hereditary breast ovarian cancer syndrome 2023-01-06 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000031217 SCV005046012 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-05-27 criteria provided, single submitter clinical testing PVS1; PM2_Supporting; PP1
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000048790 SCV005199702 pathogenic not provided 2024-01-05 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000195350 SCV005415561 pathogenic Hereditary breast ovarian cancer syndrome 2024-09-10 criteria provided, single submitter clinical testing The missense variant NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln) causes the same amino acid change as a previously established pathogenic variant. The p.Arg1699Gln variant is observed in 6/113,618 (0.0053%) alleles from individuals of gnomAD Non Finnish European background in gnomAD. The p.Arg1699Gln variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene BRCA1 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 2.32. The gene BRCA1 contains 246 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 17 variants within 6 amino acid positions of the variant p.Arg1699Gln have been shown to be pathogenic, while only 1 have been shown to be benign. The p.Arg1699Gln missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 1699 of BRCA1 is conserved in all mammalian species. The nucleotide c.5096 in BRCA1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic
OMIM RCV000031217 SCV000043748 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2011-09-25 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000031217 SCV000053817 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2013-07-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031217 SCV000145310 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Institute of Human Genetics, Medical University Innsbruck RCV000031217 SCV000212005 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 1 2016-05-01 no assertion criteria provided clinical testing
GeneReviews RCV000195350 SCV000484957 not provided Hereditary breast ovarian cancer syndrome no assertion provided literature only Intermediate risk variant
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000195350 SCV000587462 likely pathogenic Hereditary breast 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, University Hospital Cologne RCV000785422 SCV000923994 likely pathogenic Ovarian neoplasm 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ 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
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000048790 SCV002034336 pathogenic not provided no assertion criteria provided clinical testing
Center for Precision Medicine, Meizhou People's Hospital RCV002250479 SCV002520933 likely pathogenic Familial cancer of breast no assertion criteria provided literature only
BRCAlab, Lund University RCV000031217 SCV002588824 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-08-26 no assertion criteria provided clinical testing
Laboratory for Genotyping Development, RIKEN RCV003162265 SCV002758503 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research
PreventionGenetics, part of Exact Sciences RCV004554634 SCV004734896 likely pathogenic BRCA1-related disorder 2024-05-27 no assertion criteria provided clinical testing The BRCA1 c.5096G>A variant is predicted to result in the amino acid substitution p.Arg1699Gln. This variant has been reported in a large number patients and families with breast and ovarian cancer (Rostagno et al. 2003. PubMed ID: 12827452; Spurdle et al. 2012. PubMed ID: 22889855; Moghadasi et al. 2017. PubMed ID: 28490613) and at least in one individual with suspected Lynch syndrome (Table S1, Yurgelun et al. 2015. PubMed ID: 25980754). A recent study of 129 families with this variant estimated cumulative (by age 70) risks of 20% and 6% for breast and ovarian cancer, respectively (Moghadasi et al. 2017. PubMed ID: 28490613). Functional studies suggest that this variant may impair protein function (Lovelock et al. 2007. PubMed ID: 18036263; Lee et al. 2010. PubMed ID: 20516115; Bouwman et al. 2013. PubMed ID: 23867111). This variant is reported in 0.0053% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37636/). This variant is interpreted as likely pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000195350 SCV005373753 likely pathogenic, low penetrance Hereditary breast ovarian cancer syndrome 2024-10-11 no assertion criteria provided curation This variant is considered pathogenic with reduced penetrance relative to the average BRCA1 truncating pathogenic variant; According to the ClinGen ENIGMA BRCA1 v1.1.0 criteria we chose these criteria: PS3 (strong pathogenic): Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30257991, 32546644, 30765603) (PS3 met)., PM3 (supporting pathogenic): 2 Punkte, Keupp 2019, comp het in Fall mit FA, PP3 (supporting pathogenic): BayesDEL:0.419574 , PP4 (supporting pathogenic): Combined LR Score 25.495

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