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

gnomAD frequency: 0.00003  dbSNP: rs80358084

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233774	SCV000289826	benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112623	SCV001287199	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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.
GeneDx	RCV000587578	SCV001945406	benign	not provided	2015-05-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 21990134, 30209399)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149774	SCV003838745	likely benign	Breast and/or ovarian cancer	2021-11-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112623	SCV004822946	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-01	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112623	SCV000145466	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112623	SCV000189347	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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 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, susceptibility to, 1		no assertion provided	in vitro
PreventionGenetics, part of Exact Sciences	RCV004554706	SCV004709574	likely benign	BRCA1-related disorder	2020-11-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).