ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5194-12G>A (rs80358079)

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Total submissions: 9
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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) RCV000077608 SCV000244391 pathogenic 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 5 based on posterior probability = 1
Invitae RCV000048851 SCV000076864 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing This sequence change falls in intron 18 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in affected individuals with family histories of breast cancer (PMID: 10923033, 17924331, 23278966, 25682074). This variant is also known as IVS19-12G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55451). Based on multifactorial likelihood algorithms using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Experimental studies have demonstrated that this variant weakens the consensus acceptor splice site in intron 18, which leads to the use of a cryptic acceptor splice site 10 nucleotides upstream of the 5' end of exon 19 (PMID: 21394826, 21673748). This is expected to result in a frameshift in the BRCA1 mRNA and an absent or truncated protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077608 SCV000326205 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000583637 SCV000688548 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048851 SCV000699219 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-07 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5194-12G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 2/5 splice prediction tools predict that this variant creates a novel 3' splicing acceptor site. This prediction was confirmed by two independent studies by sequencing cDNA from the patients carrying the variant of interest (Whiley_2011, Wong-Brown_2013). The studies showed that the altered splicing led to the inclusion of 10bp intronic sequence generating a downstream frameshift mutation (p.His1732Phefs). This variant has been reported in multiple patients with breast cancer and family history of HBOC. This variant is absent in 121410 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including an expert panel. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762996 SCV000893441 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077608 SCV000109411 likely pathogenic Breast-ovarian cancer, familial 1 2014-02-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077608 SCV000145385 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
King Laboratory,University of Washington RCV001171437 SCV001251348 pathogenic Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research

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