ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5333-8C>T (rs80358084)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233774 SCV000289826 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000582283 SCV000688627 likely benign Hereditary cancer-predisposing syndrome 2017-11-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587578 SCV000699242 likely benign not provided 2016-08-11 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5333-8C>T variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing or ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/120812 (1/60406), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in affected individuals including one co-occurrence with a BRCA2 pathogenic variant, c.8537_8538delAG (p.Glu2846fsX22 - classified as pathogenic by LCA). In addition, multiple reputable clinical laboratories/databases and publications classify the variant as "likely benign/neutral." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as likely benign until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587578 SCV001133625 likely benign not provided 2019-02-04 criteria provided, single submitter clinical testing
Mendelics RCV000112623 SCV001140471 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112623 SCV001287199 uncertain significance Breast-ovarian cancer, familial 1 2018-01-15 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112623 SCV000145466 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112623 SCV000189347 likely benign Breast-ovarian cancer, familial 1 2013-07-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501072 SCV000591615 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The c.5333-8C>T variant has been reported in 1 of 256 chromosomes (frequency 0.002) from individuals with breast or ovarian cancer (Simard 2007); however, control chromosomes from healthy individuals were not evaluated in this study. This variant was identified in dbSNP (ID#rs80358084) “with untested allele”, in the UMD 1X as likely neutral, in the BIC database 3X as a variant of unknown clinical importance, and one in silico study classified it as neutral (Easton 2007). The c.5333-8C>T variant is located in the 3' splice region of intron 21 but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) did not predict a significant difference in splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. Therefore, this variant is classified as a variant of unknown significance.
Hereditary Cancer Genetics group,Vall d'Hebron Institute of Oncology RCV000233774 SCV000916358 benign Hereditary breast and ovarian cancer syndrome 2019-03-01 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000112623 SCV001238572 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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