ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5068A>C (p.Lys1690Gln) (rs397507239)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000225765 SCV000076769 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 1690 of the BRCA1 protein (p.Lys1690Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs397507239, ExAC 0.06%). This variant has been reported in individuals affected with breast cancer (PMID: 15365993, 18006916, 22333603, 26221963, 26689913, 27257965). ClinVar contains an entry for this variant (Variation ID: 55370). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000130370 SCV000185224 likely benign Hereditary cancer-predisposing syndrome 2019-09-05 criteria provided, single submitter clinical testing Conflicting evidence
GeneDx RCV000656791 SCV000210195 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5068A>C at the cDNA level, p.Lys1690Gln (K1690Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAA>CAA). Using alternate nomenclature, this variant has been previously published as BRCA1 5187A>C. BRCA1 Lys1690Gln has been reported in multiple breast cancer patients (Seo 2004, Ang 2007, Wong 2016, Li 2017, Park 2017, Ryu 2017). This variant was also classified as a variant of uncertain significance in a homology directed repair functional assay (Lu 2015). Functional analyses by Petitalot et al. (2018) showed this variant to result in defective homologous recombination and protein instability, while demonstrating normal nuclear localization. BRCA1 Lys1690Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT 1 domain and in a region known to interact with multiple other 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 Lys1690Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240688 SCV000265892 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048756 SCV000591566 uncertain significance not specified 2012-08-08 criteria provided, single submitter clinical testing
Color RCV000130370 SCV000683245 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765357 SCV000896622 uncertain significance 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
Integrated Genetics/Laboratory Corporation of America RCV000048756 SCV000918738 uncertain significance not specified 2018-05-04 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5068A>C (p.Lys1690Gln) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 2.9e-05 in 277198 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (2.9e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.5068A>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, predominantly of Asian origin (Ang_2007, Lang_2017, Li_2017, Lu_2015, Park_2017, Ryu_2017, Seo_2004, Wong_2016, Zhong_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.9294C>G, p.Y3098X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Lu_2015). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as "VUS - possibly benign."
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000048756 SCV001160223 uncertain significance not specified 2019-01-15 criteria provided, single submitter clinical testing The BRCA1 c.5068A>C; p.Lys1690Gln variant (rs397507239) variant is published in the medical literature in individuals with breast cancer (Ang 2007, Seo 2004, Li 2017). However, the variant has also been shown to functionally replace the wild type protein in a haploid cell culture model, indicating it is not deleterious (Findlay 2018). The variant is reported as a variant of uncertain significance by several sources and as likely benign by one source in the ClinVar database (Variation ID: 55370) and with an overall allele frequency of 0.003% (9/282724 alleles) in the Genome Aggregation Database. The lysine at this position is conserved but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the variant is uncertain at this time. References: Ang P et al. BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive strategy. Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2276-84. Findlay GM et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018 Oct;562(7726):217-222. Li G et al. Analysis of BRCA1/2 mutation spectrum and prevalence in unselected Chinese breast cancer patients by next-generation sequencing. J Cancer Res Clin Oncol. 2017 Oct;143(10):2011-2024. Seo JH et al. BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer. Hum Mutat. 2004 Oct;24(4):350.
Sharing Clinical Reports Project (SCRP) RCV000077592 SCV000109395 likely benign Breast-ovarian cancer, familial 1 2012-09-18 no assertion criteria provided clinical testing

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