ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5153-13A>G (rs45471406)

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Total submissions: 10
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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) RCV000112529 SCV000244387 benign Breast-ovarian cancer, familial 1 2015-08-10 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 = 0.0000517
Invitae RCV001088955 SCV000252820 benign Hereditary breast and ovarian cancer syndrome 2020-09-23 criteria provided, single submitter clinical testing
GeneDx RCV000421512 SCV000512316 likely benign not specified 2018-02-02 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.
Color Health, Inc RCV000580334 SCV000683262 likely benign Hereditary cancer-predisposing syndrome 2017-03-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586580 SCV000699210 benign not provided 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The c.5153-13A>G variant affects a non-conserved intronic nucleotide. Mutation taster predicts benign outcome for this variant. 5/5 in silico tools via Alamut predict this variant does not affect RNA splicing sites. Functional study showed that this variant does not affect splicing (Houdayer_BRCA1&2_HM_2012). This variant is found in 3/119788 control chromosomes at a frequency of 0.000025, which does not exceed maximal expected frequency of a pathogenic allele (0.0010005). This variant has been reported in BrC/OvC patients without evidence for causality. BIC lists one co-occurrence of variant of interest and a pathogenic BRCA1 variant in trans (c.5266dupC/p.Gln1756Profs, also cited in Judkins_2005), further supporting neutrality of our variant of interest. In addition, multiple clinical laboratory/publications classified this variant as benign. Taken together, this variant was classified as benign.
Counsyl RCV000112529 SCV000785499 likely benign Breast-ovarian cancer, familial 1 2017-08-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112529 SCV001287201 uncertain significance Breast-ovarian cancer, familial 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112529 SCV000145351 uncertain significance Breast-ovarian cancer, familial 1 1999-12-30 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112529 SCV001243672 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358351 SCV001554056 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 c.5153-13A>G variant was identified in the literature however the frequency of this variant in an affected population was not provided (Easton 2007, Houdayer 2012, Judkins 2005, Lindor 2012). The variant was also identified in dbSNP (ID: rs45471406) as "With Likely benign allele", ClinVar (classified as benign by Invitae, ENIGMA and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Color and Counsyl; as uncertain significance by BIC), and in LOVD 3.0 (4x ). The variant was identified in control databases in 4 of 245430 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111414 chromosomes (freq: 0.00003), and South Asian in 1 of 30776 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The variant occurs outside of the splicing consensus sequence and 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. The variant was identified with a co-occurring pathogenic BRCA1 variant (c.5266dupC (Alias 5385insC) (p.Gln1756Profs)), increasing the likelihood that the c.5153-13A>G variant does not have clinical significance (Judkins 2005). In addition, several Multifactorial likelihood-ratio models showed the variant has odds in favor of neutrality 6799 and posterior probability of being deleterious 5.17√ó10‚àí5 (Easton 2007, Lindor 2012). 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 likely benign.

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