ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1881C>G (p.Val627=) (rs80356838)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586671 SCV000210113 uncertain significance not provided 2017-09-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1881C>G at the DNA level. Using alternate nomenclature this variant would be defined as BRCA1 2000C>G. It is silent at the coding level, preserving a Valine at codon 627. In-silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 c.1881C>G was observed at an allele frequency of 0.012% (8/66,698) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether BRCA1 c.1881C>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165591 SCV000216325 likely benign Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing RNA Studies
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212164 SCV000600270 uncertain significance not specified 2017-06-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165591 SCV000682996 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-21 criteria provided, single submitter clinical testing This synonymous variant does not change the amino acid sequence of the BRCA1 protein. Splice site prediction tools suggest that this variant activates a cryptic splice donor site in exon 10. To our knowledge, functional and RNA studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 29310832, 29936257, 31065452; Leiden Open Variation Database). This variant has been identified in 12/282580 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212164 SCV000698895 uncertain significance not specified 2021-03-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1881C>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5' splice donor site. One predict the variant strengthens a cryptic 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251180 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.1881C>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, individuals being referred for genetic testing, and in unaffected individuals (example, Apessos_2018, de Jonge_2018, Kraemer_2019, Germani_2018, Nicolussi_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4; likely benign, n=1). At-least one of the submitters has re-classified this variant to a likely benign outcome since their previous evaluation as a VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586671 SCV001249211 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing
Invitae RCV001408201 SCV001610194 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-12 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000586671 SCV001716311 uncertain significance not provided 2019-10-25 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111719 SCV000144230 uncertain significance Breast-ovarian cancer, familial 1 2000-06-12 no assertion criteria provided clinical testing

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