ClinVar Miner

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

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Total submissions: 10
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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 2018-12-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168172 SCV000218834 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-26 criteria provided, single submitter clinical testing
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 2019-04-25 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).
Illumina Clinical Services Laboratory,Illumina RCV000239323 SCV001271927 uncertain significance Breast-ovarian cancer, familial 2 2017-10-14 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001114096 SCV001271928 uncertain significance Fanconi anemia, complementation group D1 2017-10-14 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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