ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4986+4A>C (rs80358087)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570191 SCV000660951 pathogenic Hereditary cancer-predisposing syndrome 2018-01-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA1) RCV000031200 SCV000145234 pathogenic Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031200 SCV000326081 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000480773 SCV000569472 likely pathogenic not provided 2017-02-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4986+4A>C or IVS15+4A>C and consists of an A>C nucleotide substitution at the +4 position of intron 15 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 5105+4A>C or IVS16+4A>C. Multiple in silico models predict this variant to destroy the nearby natural donor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has been observed in the germline of at least one individual with high grade serous ovarian carcinoma (Meisel 2014). BRCA1 c.4986+4A>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is conserved in mammals. Based on the currently available information, we consider BRCA1 c.4986+4A>C to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000496440 SCV000699188 pathogenic Hereditary breast and ovarian cancer syndrome 2016-09-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4986+4A>C variant involves the alteration of a highly conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant. 4/4 splice prediction tools predict a significant impact on normal splicing. This variant is absent in 121392 control chromosomes from ExAC. This variant is reported in at least four HBOC patients in literature and/or clinical databases. In one case, immunohistochemistry revealed a loss of BRCA1 protein, supporting that the variant has a functional effect on protein expression (Meisel_2014). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. This intronic nucleotide position is clinically important as A>T change the same position is pathogenic. In addition, a nearby intronic variant, c.4986+6T>C, is a known pathogenic/likely pathogenic variant. Taken together, the variant of interest is classified as Pathogenic.
Invitae RCV000496440 SCV000636003 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 25281711) and in several families affected with breast and/or ovarian cancer (PMID: 29446198). This variant is also known as IVS16+4A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 37619). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies Different variants affecting this nucleotide (c.4986+4A>G and c.4986+4A>T) have been observed in individuals with breast and/or ovarian cancer, and have been determined to be pathogenic (PMID: 23239986, 21203900). In addition, c.4986+4A>G has been shown experimentally to create an aberrant transcript by incorporating 65 intronic sequences immediately following exon 15, and results in a stop codon at residue 1676 (p.Met1663Valfs*14) (PMID: 23239986). This indicates that this nucleotide may be crucial for normal RNA splicing. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480773 SCV000605897 likely pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496440 SCV000587441 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031200 SCV000053800 pathogenic Breast-ovarian cancer, familial 1 2013-03-19 no assertion criteria provided clinical testing

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