ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5468-2A>G (rs398122699)

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Total submissions: 6
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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 RCV000077170 SCV000326324 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000637422 SCV000758879 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-11 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 22) of the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with early-onset ovarian cancer (PMID: 26028024). ClinVar contains an entry for this variant (Variation ID: 91653). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and/or protein function (PMID: 30209399). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001024146 SCV001186114 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing The c.5468-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 22 in the BRCA1 gene. This alteration has been reported in multiple individuals from a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations (Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). It has also been reported as a de novo alteration in an individual with ovarian cancer at age 39, however it is it unclear if paternity was confirmed in this study (Golmard L et al. Oncogene, 2016 Mar;35:1324-7). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). A close match alteration at this acceptor site, BRCA1 c.5468-1G>A was shown to make use of a cryptic acceptor site 11nt downstream (Baert A et al. Hum. Mutat., 2018 04;39:515-526). 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 acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as likely pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077170 SCV000108967 likely pathogenic Breast-ovarian cancer, familial 1 2009-11-09 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077170 SCV001243978 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000077170 SCV001549736 likely pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 c.5468-2A>G variant was identified in 3 of 83182 proband chromosomes (frequency: 0.00004) from individuals or families with breast or ovarian cancer (Golmard 2016, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs398122699) as "With Pathogenic, other allele", in ClinVar (classified as pathogenic by CIMBA; as likely pathogenic by Invitae and SCRP), and in LOVD 3.0 (2x as pathogenic). The variant was not identified in UMD-LSDB, database. The variant was not identified in the Genome Aggregation Database (Feb 27, 2017). The c.5468-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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