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

Total submissions: 8

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).