ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8332-1G>C

dbSNP: rs397507979
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002433533 SCV002677156 likely pathogenic Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing The c.8332-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 18 of the BRCA2 gene. This alteration was identified in one family of Scottish/Northern Irish descent with early onset breast and/or ovarian cancer (Scottish/Northern Irish BRCA1/BRCA2 Consortium, Br. J. Cancer 2003 Apr; 88(8):1256-62). 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 unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002496696 SCV002812413 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3 2021-12-14 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577132 SCV000678824 not provided Familial cancer of breast no assertion provided literature only
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356312 SCV001551446 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing The BRCA2 c.8332-1G>C variant was identified in 1 of 214 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer (S/N Consortium 2003). The variant was also identified in dbSNP (ID: rs397507979) as “With Pathogenic, untested allele”, ClinVar (unclassified), and ARUP Laboratories (definitely pathogenic). The variant was not identified in Clinvitae, COGR, Cosmic, LOVD 3.0, UMD-LSDB, BIC Database, or Zhejiang University databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.8332-1G>C 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 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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