ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1881C>G (p.Val627=) (rs80356838)

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Total submissions: 6
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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 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212164 SCV000600270 uncertain significance not specified 2017-06-13 criteria provided, single submitter clinical testing
Color RCV000165591 SCV000682996 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586671 SCV000698895 uncertain significance not provided 2017-08-14 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1881C>G (p.Val627Val) variant (alternatively also known as 2000C>G) involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict significant activation of a new splice donor site. ESE finder predicts that this variant creates a new site for SRp40. However, these predictions have yet to be confirmed by functional studies. This variant was found in 8/121278 control chromosomes from ExAC, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00012 (8/66698). This frequency is lower times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). One publication utilized information theory to predict the variant to strengthen a splice site in line with results from in silico prediction tools (Mucaki_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. To our knowledge, the variant has not been reported in affected individuals in literature; however it has been reported in HBOC patients by submitters in ClinVar. Taken together, this variant is currently classified as Variant of Uncertain Significance (VUS).
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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