ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4986+6T>C (rs80358086)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048724 SCV000076737 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change affects a highly conserved nucleotide near the donor splice site in intron 15. It does not directly change the encoded amino acid sequence of the BRCA1 protein. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with breast and ovarian cancer (PMID: 10406662, 21324516, 21965345, 21120943, 24729269). This variant is also known as IVS16+6T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 37620). Experimental studies have shown that this sequence change creates an aberrant transcript by activating a cryptic splice donor site. The transcript incorporates 65 bases of intronic sequence immediately following exon 15, resulting in a stop codon at residue 1676 (p.Met1663Valfs*14) (PMID: 10406662, 22505045). A different variant affecting this nucleotide (c.4986+6T>G, also known as IVS16+6T>G) has been reported in patients affected with breast and ovarian cancer (PMID: 11179017, 22160602). Also, an experimental study has shown that this variant causes the same altered splicing resulting from the c.4986+6T>C sequence change (PMID: 16619214), indicating that this nucleotide may be crucial for normal RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131837 SCV000186892 pathogenic Hereditary cancer-predisposing syndrome 2014-02-21 criteria provided, single submitter clinical testing
GeneDx RCV000159997 SCV000210190 pathogenic not provided 2018-07-09 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4986+6T>C or IVS15+6T>C and consists of a T>C nucleotide substitution at the +6 position of intron 15 of the BRCA1 gene. This variant, also referred to as BRCA1 5105+6T>C or IVS16+6T>C using alternate nomenclature, has been observed in multiple individuals with personal and/or family histories consistent with Hereditary Breast and Ovarian Cancer (Scholl 1999, Akbari 2011, Lynce 2015, Pal 2015, Rummel 2017). Functional studies demonstrate that BRCA1 c.4986+6T>C leads to activation of a downstream cryptic splice donor site, which results in an aberrant RNA transcript and a truncated protein (Scholl 1999, Uchikawa 2007). Another variant at the same position, BRCA1 c.4986+6T>G, was also shown to result in an abnormal splicing (Chen 2006). Based on currently available evidence, we consider this variant to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735559 SCV000219254 pathogenic Breast and/or ovarian cancer 2017-03-03 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031201 SCV000326085 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000159997 SCV000484492 likely pathogenic not provided 2015-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000031201 SCV000677655 likely pathogenic Breast-ovarian cancer, familial 1 2017-04-01 criteria provided, single submitter clinical testing
Color RCV000131837 SCV000683231 pathogenic Hereditary cancer-predisposing syndrome 2016-05-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000159997 SCV000693498 likely pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048724 SCV000699190 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-16 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4986+6T>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict loss/weakening effect on the canonical splicing donor site. These predictions were proved by a functional study that observed the consequence of this variant was to use a cryptic site 65nt downstream of the 5'ss and this variant was therefore classified as have severe impact on splicing (Houdayer_2012). This variant is absent in 121390 control chromosomes. This variant has been reported in many affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031201 SCV000744604 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031201 SCV000053801 pathogenic Breast-ovarian cancer, familial 1 2012-02-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031201 SCV000145238 not provided Breast-ovarian cancer, familial 1 no assertion provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048724 SCV000587440 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031201 SCV000733602 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735559 SCV000863697 likely pathogenic Breast and/or ovarian cancer 2015-05-06 no assertion criteria provided clinical testing

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