ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8042C>G (p.Thr2681Arg) (rs587782519)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131690 SCV000186726 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000168172 SCV000218834 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 2681 of the BRCA2 protein (p.Thr2681Arg). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and arginine. 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: 142520). 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: "Deleterious"; 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724545 SCV000226715 uncertain significance not provided 2015-01-09 criteria provided, single submitter clinical testing
GeneDx RCV000724545 SCV000279383 uncertain significance not provided 2018-10-05 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8042C>G at the cDNA level, p.Thr2681Arg (T2681R) at the protein level, and results in the change of a Threonine to an Arginine (ACA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 8270C>G. This variant has been observed in at least one family with breast and/or ovarian cancer (Lu 2012). Additionally, this variant was identified as a somatic variant in a breast tumor and was predicted to be of uncertain significance by a model based on tumor pathology, hormone receptor status, tumor grade, loss of heterozygosity, and presence of deleterious variants in trans (Spearman 2008). BRCA2 Thr2681Arg was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Thr2681Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000724545 SCV000296671 uncertain significance not provided 2019-07-12 criteria provided, single submitter clinical testing
Color RCV000131690 SCV000689092 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
Counsyl RCV000239323 SCV000786342 uncertain significance Breast-ovarian cancer, familial 2 2018-04-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781102 SCV000918933 uncertain significance not specified 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8042C>G (p.Thr2681Arg) variant involves the alteration of a conserved nucleotide and it is located in the oligonucleotide/oligosaccharide-binding 1 domain/OB-fold (InterPro) of the protein. 4/4 in silico tools predict a damaging outcome for this variant. One study showed that this variant has a weak impact on splicing, with the canonical transcript at approximately 97.7% (Fraile-Bethencourt_BRCA2_PLOS_2017). This variant is absent in 245992 control chromosomes from gnomAD. The variant was reported in two patients with breast cancer (Spearman_2008, Lu_2012), without strong evidence for causality. Multiple clinical diagnostic centers classify the variant as a VUS. Taken together, this variant is currently classified as Variant of Uncertain Significance (VUS).

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