ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3101T>C (p.Ile1034Thr) (rs545974734)

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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 RCV000218639 SCV000274670 uncertain significance Hereditary cancer-predisposing syndrome 2015-03-24 criteria provided, single submitter clinical testing
Color RCV000218639 SCV000911756 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000589055 SCV000569865 uncertain significance not provided 2018-06-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3101T>C at the cDNA level, p.Ile1034Thr (I1034T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 3329T>C. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Ile1034Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRC1 and the RAD51 binding domains (Cole 2011, Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Ile1034Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589055 SCV000694666 uncertain significance not provided 2016-06-30 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3101T>C (p.Ile1034Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/120352 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. 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.
Invitae RCV000474468 SCV000549839 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1034 of the BRCA2 protein (p.Ile1034Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs545974734, ExAC 0.009%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 230962). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
PreventionGenetics RCV000589055 SCV000805685 uncertain significance not provided 2016-11-02 criteria provided, single submitter clinical testing

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