ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.619A>G (p.Thr207Ala) (rs80358858)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167341 SCV000218193 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-12 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000113897 SCV000147311 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590491 SCV000694947 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing Variant Summary: This substitution involves a nucleotide conserved among species. It is located 12bp away from the exon7/intron7 boundary. ESE site prediction tool via Alamut predict that this variant may change the binding of ESEs (SF2/ASF and SRp40), however, 5/5 in silico splice prediction tools via Alamut predict no significant effect on splicing. The predicted neutral impact on splicing was confirmed by the studies of Soukarieh_2016, Di Giacomo_2013, and Sanz_2010; all of the studies showed that the variant does not induce skipping of exon 7. The variant of interest results in replacement of a medium sized, polar Threonine with a small size, hydrophobic Alanine (A). A functional study showed that the T207 residue is a substrate of Plk1 and is phosphorylated on an M phase specific manner (Lin_2003). Another functional study (Mondal_2012) showed that the variant does not impair the recruitment of Alix and Tsg101 to the midbody and formation of CEP55-Alix and CEP55-Tsg101 complexes during cytokinesis. Due to the uncertainty of the role of the above mentioned functions in the etiology of HBOC, these functional studies do not permit the establishment of a cause-effect relationship between the variant and HBOC. In addition, the variant is absent in the large and broad cohorts of the NHLBI-ESP and ExAC projects and has not been reported in HBOC patients either. Multiple clinical laboratories and reputatble databases classified this variant as VUS. Due to the absence of clinical, population-based data and the uncertain relevance of the reported functional impacts in the HBOC etiology, the variant of interest is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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