ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9857T>A (p.Ile3286Asn) (rs398122624)

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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 RCV000164700 SCV000215368 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
GeneDx RCV000215513 SCV000279861 uncertain significance not provided 2016-02-05 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9857T>A at the cDNA level, p.Ile3286Asn (I3286N) at the protein level, and results in the change of an Isoleucine to an Asparagine (ATT>AAT). Using alternate nomenclature, this variant would be defined as BRCA2 10085T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile3286Asn 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 Isoleucine and Asparagine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ile3286Asn occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Ile3286Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000537252 SCV000635763 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 3286 of the BRCA2 protein (p.Ile3286Asn). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91536). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Sharing Clinical Reports Project (SCRP) RCV000077053 SCV000108850 uncertain significance Breast-ovarian cancer, familial 2 2011-10-28 no assertion criteria provided clinical testing

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