ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.516G>A (p.Lys172=) (rs80359790)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044583 SCV000072596 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-11-08 criteria provided, single submitter clinical testing This sequence change affects codon 172 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. It also falls at the last nucleotide of exon 6 of the BRCA2 coding sequence. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with breast and ovarian cancers (PMID: 19267246). ClinVar contains an entry for this variant (Variation ID: 51795). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, and this prediction has been confirmed by a published transcriptional study in patient-derived RNA and in functional studies using exon trapping analysis in transfected cells (PMID: 19267246). In summary, this is a rare silent change that has been reported in an affected individual and has been shown to affect RNA splicing. However, in the absence of clinical evidence to prove the impact of this change on disease causation, it has been classified as a Variant of Uncertain Significance.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113726 SCV000327154 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023653 SCV001185564 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-06 criteria provided, single submitter clinical testing The c.516G>A variant (also known as p.K172K), located in coding exon 5 of the BRCA2 gene, results from a G to A substitution at nucleotide position 516. This nucleotide substitution does not change the lysine at codon 172. However, this change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. This variant, designated 744G>A/c.516G>A (Lys172Lys), was shown to result in skipping of exon 6 or exons 5 and 6 in a minigene assay, resulting in premature termination at codon 168 or 154, respectively. It was identified in a Danish patient with breast cancer diagnosed at 37 and 65 years old; her family history was significant for male breast cancer in her father and ovarian cancer in a paternal aunt (Hansen TV et al. Breast Cancer Res. Treat. 2010 Feb;119:547-50). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284089 SCV001469688 uncertain significance not provided 2019-09-30 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113726 SCV000147045 uncertain significance Breast-ovarian cancer, familial 2 2001-10-29 no assertion criteria provided clinical testing

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