ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3994C>G (p.His1332Asp) (rs863224588)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000775953 SCV000910459 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing
GeneDx RCV000588273 SCV000572279 uncertain significance not provided 2016-11-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3994C>G at the cDNA level, p.His1332Asp (H1332D) at the protein level, and results in the change of a Histidine to an Aspartic Acid (CAT>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 4222C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 His1332Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 His1332Asp occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 His1332Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588273 SCV000694734 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3994C>G (p.His1332Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution that does not lie within a known functional domain (InterPro). 3/5 in silico tools predict a benign outcome for this variant. This variant is absent from the large control database ExAC (0/112012 control chromosomes). One clinical diagnostic laboratory has classified this variant as one of uncertain significance. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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