ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5278-14C>G (rs80358105)

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Total submissions: 16
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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) RCV000077162 SCV001161517 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 7.93E-10
Counsyl RCV000077162 SCV000154025 likely benign Breast-ovarian cancer, familial 1 2014-03-12 criteria provided, single submitter literature only
Michigan Medical Genetics Laboratories,University of Michigan RCV000077162 SCV000195939 likely benign Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
Invitae RCV000206737 SCV000260046 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000421300 SCV000512318 benign not specified 2015-06-19 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Baylor Genetics RCV000470071 SCV000540990 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000580942 SCV000683280 likely benign Hereditary cancer-predisposing syndrome 2015-07-20 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077162 SCV000744587 likely benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000421300 SCV000918752 likely benign not specified 2018-05-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5278-14C>G alters a non-conserved nucleotide resulting in intronic change at a position not widely known to affect normal splicing. 5/5 computational tools predict no significant impact on normal splicing, which were confirmed by multiple studies. The frequency of this variant in general population (gnomAD dataset) is lower than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (3.3e-05 vs 0.001), allowing no conclusion about variant significance. The c.5278-14C>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.5722_5723delCT, p.Leu1908Argfs (BIC); BRCA2 unspecified (van der Hout_2006)), providing supporting evidence for a benign role. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000077162 SCV000108959 likely benign Breast-ovarian cancer, familial 1 2011-01-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077162 SCV000145433 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353929 SCV000591607 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The c.5278-14C>G variant was identified in 5 of 8294 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian and pancreatic cancer (Axilbund 2009, Spearman 2008, van der Hout 2006). The variant was also identified in dbSNP (ID: rs80358105), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a likely benign variant by the Sharing Clinical Reports Project (derived from Myriad reports) and Counsyl; classified as unknown clinical importance by BIC), the BIC database (4X with unknown clinical importance), and UMD (3X as an uncertain significance variant). This variant was identified in the Exome Variant Server project in 3 of 13006 European American/African American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 4 of 76380 chromosomes (4 individuals) from a population of European (Non-Finnish) and African individuals, although this low number of observations is not substantive enough to determine its relationship to disease. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Four studies have predicted the variant has no effect on splicing (Spearman 2008, Steffensen 2014, van der Hout 2006, Whiley 2011) and two of them classified it as neutral (Steffensen 2014, van der Hout 2006). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077162 SCV000733589 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077162 SCV001242541 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV001689620 SCV001906130 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000421300 SCV001958300 benign not specified no assertion criteria provided clinical testing

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