ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5068A>C (p.Lys1690Gln) (rs397507239)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000225765 SCV000076769 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-16 criteria provided, single submitter clinical testing
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 Breast neoplasm 2015-11-01 criteria provided, single submitter research
Color Health, Inc RCV000130370 SCV000683245 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-21 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048756 SCV000918738 likely benign not specified 2021-04-10 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. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Cline_2019). The variant allele was found at a frequency of 3.2e-05 in 251460 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5068A>C, has been reported in the literature in individuals affected with breast and/or ovarian Cancer, predominantly of Asian origin (example, 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 Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported (BRCA2 c.9294C>G, p.Y3098X, Wong_2016), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair (example, Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). At-least two submitters have re-classified this variant as likely benign since its previous evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely 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.
Breast Center,Key Laboratory of Carcinogenesis and Translational Research RCV000225765 SCV001430335 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-05-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077592 SCV000109395 likely benign Breast-ovarian cancer, familial 1 2012-09-18 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353418 SCV000591566 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Lys1690Gln variant was identified in 11 of 23576 proband chromosomes (frequency: 0.0005) from Asian individuals or families with breast and/or ovarian cancer and was present in 12 of 22482 control chromosomes (frequency: 0.0005) from healthy individuals (Momozawa 2018, Bhaskaran 2019, Ang 2007). The variant was also identified in dbSNP (ID: rs397507239) as "With Pathogenic, Uncertain significance allele", however it is noted that there is an alternate variant resulting in a stop codon at this position to which the pathogenic classification likely refers, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Color, Invitae and 3 other submitters; and as likely benign by SCRP), LOVD 3.0 (4 entries), UMD-LSDB (1 entry). The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 8 of 277098 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 8 of 18864 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. In a homology-directed repair assay this variant was shown to have activity comparable to wild type, though insufficient data was available to determine if the finding was statistically significant (Lu 2015). Protein sequence analysis suggests that Lys1690 plays a role in conjugation with small ubiquitin-like modifiers (SUMO) within the BRCT domain though the authors acknowledge that the exact site of conjugation remains unclear (Vialter 2011). The p.Lys1690 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Brotman Baty Institute,University of Washington RCV000077592 SCV001242037 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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