ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.681+4A>G (rs397507884)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258477 SCV000327520 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564042 SCV000661243 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-23 criteria provided, single submitter clinical testing The c.681+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 7 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site and create a new alternate splice donor site. Splicing studies from both human lymphoblastoid cell lines and minigene show that this variant results in use of the predicted alternate donor site leading to a frameshift with predicted premature truncation (Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38; Fraile-Bethencourt E et al. J. Pathol., 2019 Aug;248:409-420). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589335 SCV000694998 pathogenic Hereditary breast and ovarian cancer syndrome 2019-04-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.681+4A>G 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: Four predict the variant abolishes/weakens a 5' donor site. Four predict the variant strengthens a cryptic intronic 5 donor site. These predictions were confirmed by experimental evidence demonstrating the variant to improve an intronic cryptic donor site resulting in the insertion of 4 nucleotides which causes a frameshift (p.N228Vfs*11) (Fraile-Bethencourt_2019, Houdayer_2012). The variant was absent in 237674 control chromosomes (gnomAD). c.681+4A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). These data indicate that the variant is likely associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (1x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Health, Inc RCV000564042 SCV001358249 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-29 criteria provided, single submitter clinical testing
Invitae RCV000589335 SCV001484289 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-30 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 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 a family affected with breast cancer (PMID: 22762150). The variant is also known as c.IVS8+4A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 52193). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this change disrupts the consensus splice site and affects splicing (PMID: 22505045). 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.

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