Submissions for variant NM_000059.4(BRCA2):c.8042C>G (p.Thr2681Arg)

gnomAD frequency: 0.00001  dbSNP: rs587782519

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131690	SCV000186726	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-03	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. 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 variant was found to be functional in a mouse embryonic stem cell complementation and drug sensitivity assay (Biswas K et al. NPJ Genom Med 2020 Dec;5(1):52). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168172	SCV000218834	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724545	SCV000226715	uncertain significance	not provided	2015-01-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000724545	SCV000279383	uncertain significance	not provided	2023-05-22	criteria provided, single submitter	clinical testing	Published functional studies suggest no impact on function: performed similar to wild type in cell survival and drug-sensitivity assays (Biswas et al., 2020); Observed in individuals with a personal or family history including breast and/or ovarian cancer (Lu et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8270C>G; This variant is associated with the following publications: (PMID: 18951461, 18824701, 28339459, 29884841, 31853058, 32377563, 31131967, 12228710, 22476429, 33293522)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724545	SCV000296671	uncertain significance	not provided	2019-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131690	SCV000689092	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 2681 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study in mouse embryonic stem cells showed that this variant did not impact cell viability or drug sensitivity (PMID: 33293522). This variant has been reported in individuals with a personal or family history of breast or ovarian cancer (PMID: 18824701, 22476429) and in a multifactorial analysis with tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.690, 1.102 and 0.858, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl	RCV000239323	SCV000786342	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781102	SCV000918933	uncertain significance	not specified	2023-05-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8042C>G (p.Thr2681Arg) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251192 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8042C>G has been reported in the literature in individuals affected with breast cancer (example, Spearman_2008, Lu_2012), but has also been reported at a carrier frequency of 0.0001365 in a cohort of European American women over the age of 70 with no history of cancer (FLOSSIES dataset). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been observed at our laboratory (CHEK2 c.283C>T, p.Arg95X; BRCA2 c.1755_1759delGAAAA, p.Lys585AsnfsX3), providing supporting evidence for a benign role. 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). Additionally, one functional study showed no damaging effect of this variant by cell survival and drug sensitivity (Biswas_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33293522, 28339459, 22476429, 18824701). Eight ClinVar submitters have assessed this variant since 2014: seven classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Illumina Laboratory Services, Illumina	RCV000239323	SCV001271927	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 Laboratory Services, 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.
Baylor Genetics	RCV003462020	SCV004213595	uncertain significance	Familial cancer of breast	2024-02-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000239323	SCV004845593	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 2681 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study in mouse embryonic stem cells showed that this variant did not impact cell viability or drug sensitivity (PMID: 33293522). This variant has been reported in individuals with a personal or family history of breast or ovarian cancer (PMID: 18824701, 22476429) and in a multifactorial analysis with tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.690, 1.102 and 0.858, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.