ClinVar Miner

Submissions for variant NM_007300.4(BRCA1):c.693G>A (p.Thr231=) (rs62625298)

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Total submissions: 12
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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) RCV000144222 SCV000578247 likely benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae RCV000588682 SCV000077112 benign not provided 2019-02-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131383 SCV000186359 likely benign Hereditary cancer-predisposing syndrome 2017-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown)
GeneDx RCV000588682 SCV000210083 uncertain significance not provided 2018-09-25 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.693G>A at the DNA level. Although this variant is silent at the coding level, preserving a Threonine at codon 231, it has been demonstrated to affect splicing. Brandao et al. (2011) and Raponi et al. (2012) determined that this variant leads to a significant reduction in the levels of the full length BRCA1 transcript and increases the levels of the D(11) isoform (a BRCA1 transcript with the deletion of exon 11, using alternate exon numbering). However, the deletion of exon 11 in the D(11) isoform is an in-frame deletion present in multiple tissues from control individuals (Orban 2003, Colombo 2014). Therefore, the significance of this finding is unknown. This variant, also defined as 812G>A using alternate nomenclature, was observed in at least two individuals with a personal history of breast cancer (Borg 2010, Brandao 2011). This variant was observed at an allele frequency of 0.02% (1/6404) in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether BRCA1 c.693G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Michigan Medical Genetics Laboratories,University of Michigan RCV000144222 SCV000267686 benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000159943 SCV000538446 uncertain significance not specified 2016-03-29 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent, not in splice site. ExAC: 1/5842 Finnish chromosomes; ClinVar: 2 labs B/LB, 2 labs VUS; 1 paper investigating constraint against synonymous substitutions in BRCA exon 11
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000159943 SCV000591297 uncertain significance not specified 2012-11-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159943 SCV000600433 uncertain significance not specified 2017-03-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588682 SCV000699294 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.693G>A (p.Thr231Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. The variant is not found within a known functional domain (InterPro) and one in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may create SRp40 and SF2/ASF ESE sites. An in vitro study of SF2/ASF binding to the locus suggests the opposite of this prediction, where SF2/ASF binds the WT sequence but not the variant sequence (Tammaro_IJMS_2014). This variant was found in the large control population database ExAC (4/99890 control chromosomes) at a frequency of 0.00004, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Multiple clinical diagnostic laboratories/reputable databases have conflicting classifications for this variant, including benign (SCRP, Michigan Medical Genetics), likely benign (Invitae, Ambry), and uncertain significance (GeneDx, LOVD3.0, UMD). In addition, several published studies have tested the effect of the variant on splicing and found the variant alters exon 11 skipping, though the physiological consequence of this alteration is unknown since exon 11 skipping also occurs in normal tissue. Given the conflicting classifications and the unknown physiological consequences of altered splicing at exon 11, the variant is classified as a VUS until more information becomes available.
Color RCV000131383 SCV000902683 likely benign Hereditary cancer-predisposing syndrome 2014-12-12 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000144222 SCV000189350 benign Breast-ovarian cancer, familial 1 2011-03-02 no assertion criteria provided clinical testing
True Health Diagnostics RCV000131383 SCV000805236 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-06 no assertion criteria provided clinical testing

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