ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.301+6T>C (rs753859240)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000210142 SCV000266156 uncertain significance Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000234331 SCV000289768 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-09 criteria provided, single submitter clinical testing This sequence change falls in intron 5 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 present in population databases (rs753859240, ExAC 0.004%). This variant has been reported in an individual affected with ovarian cancer (PMID: 26845104). It has also been reported in a single family with multiple individuals affected with breast cancer, ovarian cancer or other types of cancer. Currently there is insufficient evidence to conclude whether this variant segregates with disease (PMID: 21769658). ClinVar contains an entry for this variant (Variation ID: 224562). Based on a multifactorial likelihood algorithm using genetic, in silico and statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 21769658). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis from patient-derived cells detected very low levels of an aberrant transcript resulting in an in-frame change of 4 amino acids (PMID: 21769658). However, a saturation genome assay for functional classification of BRCA1 variants indicates that this variant affects BRCA1 RNA splicing and/or protein function (PMID: 30209399). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507484 SCV000600312 uncertain significance not specified 2016-11-29 criteria provided, single submitter clinical testing
Color RCV000584261 SCV000688411 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000507484 SCV000698994 uncertain significance not specified 2019-01-31 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.301+6T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predicts that the variant abolishes a 5' splicing donor site. This is supoprted by a study reporting very low levels of aberrant transcript, possibly resulting from use of a cryptic site at c.292, 9 nucleotides upstream from canonical 5' splice donor site (Thomassen_2011). The variant allele was found at a frequency of 1.2e-05 in 245948 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.301+6T>C has been reported in the literature in an individual affected with ovary cancer (Shirts_2015) and in an individual affected with breast cancer and with a family history of breast and ovarian cancer and other cancers including lung cancer, layrynx cancer and myeloma however, without evidence of co-segregation of the variant with disease (Thomassen_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Experimental evidence evaluating an impact on protein function through assessment of functional homology-directed DNA repair (HDR) pathway reported the variant with a functional score supporting loss of function (Findlay_2018). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Brotman Baty Institute,University of Washington RCV000210142 SCV001238610 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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