ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.693G>A (p.Thr231=) (rs62625298)

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Total submissions: 13
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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 RCV001080079 SCV000077112 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131383 SCV000186359 likely benign Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159943 SCV000600433 uncertain significance not specified 2017-03-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000159943 SCV000699294 likely benign not specified 2020-01-31 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.693G>A results in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, multiple publications reports experimental evidence that this variant affects mRNA splicing, with the variant determining exon 11 skipping and a marked increase in amounts of the D(11) isoform (Brandao_2011, Raponi_2012, Tammaro_2014). The physiological consequences of this alteration are unknown since exon 11 skipping also occurs in normal breast tissue. The variant allele was found at a frequency of 6.9e-05 in 247680 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.9e-05 vs 0.001), allowing no conclusion about variant significance. c.693G>A has been reported in the literature in sequencing studies of individuals affected with Hereditary Breast and Ovarian Cancer (example, Borg_2010, Brandao_2011, Song_2006, Momozawa_2018, Kraemer_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One recently published case control association study of Japanese individuals showed no association of this variant with breast cancer in males and females (Momozawa_2019). At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.6082_6086delGAAGA, p.Glu2028LysfsX19), providing supporting evidence for a benign role. 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 (benign, n=2; likely benign, n=2; VUS, n=4). Some of these submitters provide overlapping evidences utilized in the context of this evaluation. We have observed this variant at a frequency of 0.01% in our tested cohort and previously classified the variant as a VUS weighting the reported splicing evidence in our evaluation. However, in over two years since its initial evaluation, we have not observed any additional evidence supporting a pathogenic outcome and at-least one additional report supporting no association with breast cancer has been ascertained (Momozawa_2018). Based on the evidence outlined above, the variant was re-classified as likely benign.
Color Health, Inc RCV000131383 SCV000902683 likely benign Hereditary cancer-predisposing syndrome 2014-12-12 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588682 SCV001501184 likely benign not provided 2020-07-01 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353729 SCV000591297 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Thr231= variant was identified in 5 of 20638 proband chromosomes (frequency: 0.0002) from individuals or families with breast and ovarian cancer and was present in 5 of 47462 control chromosomes (frequency: 0.0001) from healthy individuals (Momozawa 2018, Borg 2010, Brandao 2011, Song 2006). The variant was also identified in dbSNP (ID: rs62625298) as "With Likely benign, Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx and 5 other submitters; as likely benign by ENIGMA expert panel in 2017 and Ambry Genetics; and as benign by Invitae and 2 other submitters), LOVD 3.0 and in UMD-LSDB (15 records, neutral classification). In UMD, the variant was reported as co-occurring with a pathogenic BRCA2 variant (c.6082_6086del, p.Glu2028Lysfs*19), increasing the likelihood that the p.Thr231= variant does not have clinical significance. It was identified in control databases in 22 of 274654 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23876 chromosomes (freq: 0.00004), Other in 1 of 6404 chromosomes (freq: 0.0002), Latino in 2 of 34158 chromosomes (freq: 0.00006), European in 14 of 125226 chromosomes (freq: 0.0001), and Finnish in 4 of 25642 chromosomes (freq: 0.0002), while it was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. This variant was demonstrated to result in partial exon 11 skipping by RT-PCR and mini-gene assays, although the biological significance of the change in the ratio of splicing isoforms is unclear (Brandao 2011, Raponi 2012, Tammaro 2015). The p.Thr231= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, 1 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.
True Health Diagnostics RCV000131383 SCV000805236 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-06 no assertion criteria provided clinical testing

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