ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5120C>T (p.Thr1707Ile) (rs786202354)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165119 SCV000215829 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000165119 SCV000911757 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-11 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000479876 SCV000591943 uncertain significance not specified 2014-07-22 criteria provided, single submitter clinical testing
GeneDx RCV000767034 SCV000572340 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5120C>T at the cDNA level, p.Thr1707Ile (T1707I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 5348C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr1707Ile 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 Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr1707Ile occurs at a position that is not conserved and is located in the RAD51 binding domain and POLH binding domain (Roy 2012, Buisson 2014). 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 Thr1707Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000709315 SCV000948507 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1707 of the BRCA2 protein (p.Thr1707Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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: 185662). 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 tolerated, 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.
Mendelics RCV000709315 SCV000838805 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing

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