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

Total submissions: 10

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	The p.T2681R variant (also known as c.8042C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8042. The threonine at codon 2681 is replaced by arginine, an amino acid with similar properties. This alteration was reported in a study aiming to distinguish between sporadic and germline alterations in breast/ovarian tumors without the need for familial testing or segregation analysis; it was detected in a breast tumor and remained classified as a variant of unknown significance (Spearman AD et al. J. Clin. Oncol. 2008 Nov 20;26(33):5393-400). In another study, this variant was seen in 1/146 patients with breast cancer from high risk families, with at least two first- and second-degree relatives diagnosed with breast and/or ovarian cancer (Lu W et al. Fam. Cancer. 2012 Sep;11(3):381-5). A study utilizing a splicing reporter minigene assay found this alteration to have a weak impact on splicing (Fraile-Bethencourt E et al. PLoS Genet., 2017 Mar;13:e1006691). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 Health, Inc	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.