ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8165C>G (p.Thr2722Arg) (rs80359062)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031723 SCV000244480 pathogenic Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Ambry Genetics RCV000163026 SCV000213514 pathogenic Hereditary cancer-predisposing syndrome 2019-05-01 criteria provided, single submitter clinical testing The p.T2722R pathogenic mutation (also known as c.8165C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8165. The threonine at codon 2722 is replaced by arginine, an amino acid with similar properties. <span style="background-color:initial">This alteration has been reported in a 38-year breast cancer patient, her affected sister and their affected mother (Fackenthal J et al. Am J Hum Genet. 2002 Sep;71(3):625-31). This same study also demonstrated that this alteration results in decreased protein function and incomplete skipping of exon 18, which was corroborated by several other functional studies (Fackenthal J et al. Am J Hum Genet. 2002 Sep;71(3):625-31, Farrugia D et al. Cancer Res. 2008 May 1;68(9):3523-31, Kuznetsov S et al. Nat Med. 2008 Aug;14(8):875-81, Sanz D et al. Clin Cancer Res. 2010 Mar 15;16(6):1957-67, Guidugli L et al. Cancer Res. 2013 Jan 1;73(1):265-75). Additionally, a homology-directed DNA repair (HDR) assay demonstrated p.T2722R to have low functionality, with a probability of pathogenicity of 0.99 (Guidugli L et al. Am. J. Hum. Genet. 2018 Feb;102(2):233-248).<span style="background-color:initial"> In addition, this alteration is located in the highly conserved oligonucleotide binding domain (Karchin R et al Cancer Inform. 2008;6:203-16). This alteration has been classified as pathogenic (p>0.9975) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8). <span style="background-color:initial"> Of note, this alteration is also designated as 8393C>G in published literature. <span style="background-color:initial">Based on the available evidence, this alteration is classified as a pathogenic mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031723 SCV000327824 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000405476 SCV000383780 likely pathogenic BRCA2-Related Disorders 2017-05-22 criteria provided, single submitter clinical testing The BRCA2 c.8165C>G (p.Thr2722Arg) variant has been reported in three studies in which it is found in a heterozygous state in a mother and her two daughters, all of whom were diagnosed with early onset breast and/or ovarian cancer, in a heterozygous state in two individuals with breast cancer and a risk family profile indicative of HBOC or family history of breast cancer (Fackenthal et al. 2002; van der Hout et al. 2006; Meisel et al. 2017). Control data are unavailable for this variant, which, despite good coverage in the region, is also not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database. RT-PCR analysis of patient derived mRNA showed that the p.Thr2722Arg variant resulted in skipping of exon 18 which produced a shorter transcript than wild type that was predicted to cause a premature truncation of the BRCA2 protein (Fackenthal et al. 2002). In a subsequent study the full length wild type transcript was shown to be more abundant (Kuznetsov 2008). The p.Thr2722Arg variant protein demonstrated impaired BRCA2 protein function in a homology-directed DNA break repair assay as well as an embryonic stem cell based survival assay (Guidugli et al. 2014; Hendriks et al. 2014). Kuznetsov et al. (2008) demonstrated that the variant failed to rescue mouse ES-cell lethality. In addition, a different variant at the same nucleotide position resulting in a different amino acid change was reported in an individual with breast cancer and classified as likely pathogenic (Yadav et al. 2016). Based on the collective evidence, the p.Thr2722Arg variant is classified as likely pathogenic for hereditary breast and ovarian cancer. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000414368 SCV000490435 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8165C>G at the cDNA level, p.Thr2722Arg (T2722R) at the protein level, and results in the change of a Threonine to an Arginine (ACA>AGA). This variant, also reported as BRCA2 8393C>G using alternate nomenclature, has been reported in at least three familial breast/ovarian cancer families, segregating with disease in at least one kindred (Fackenthal 2002, van der Hout 2006, Meisel 2017). This variant was found to cause skipping of exon 18, possibly due to disruption of an exonic splice enhancer (Fackenthal 2002). However, studies quantifying the amount of mutant and wild-type transcript produced found the full length wild-type transcript to be more abundant (Kuznetsov 2008, Sanz 2010). When present in the full length transcript, BRCA2 Thr2722Arg impairs homology-directed repair activity, leads to increased centrosome amplification, and is unable to rescue cell growth in complementation assays (Farrugia 2008, Kuznetsov 2008, Guidugli 2013, Hendriks 2014). BRCA2 Thr2722Arg was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). Although in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function, the variant was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations. Based on currently available evidence, we consider this variant to be pathogenic.
Color Health, Inc RCV000163026 SCV000689101 likely pathogenic Hereditary cancer-predisposing syndrome 2020-11-06 criteria provided, single submitter clinical testing This missense variant replaces threonine with arginine at codon 2722 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). RNA studies found that this variant causes partial exon 18 skipping in patient-derived RNA (PMID: 18607349, 12145750) and in vitro minigene splicing assay (PMID: 20215541). Functional studies reported the full-length variant protein to be defective in homology-directed DNA repair, centrosome duplication and BRCA2-null mouse embryonic cell complementation assays (PMID: 18451181, 18607349, 23108138, 25146914). This variant has been observed in individuals affected with personal and/or family history of breast/ovarian cancer (PMID: 12145750, 16683254, 27878467, 28324225). This variant also has been reported in multifactorial analysis as pathogenic (PMID: 23108138, 18451181) based in part on cosegregation and family history likelihood ratios of 10.8 and 6.95, respectively (PMID: 23108138). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000414368 SCV000887932 pathogenic not provided 2017-09-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193120 SCV001361756 pathogenic Hereditary breast and ovarian cancer syndrome 2019-06-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8165C>G (p.Thr2722Arg) 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. Several computational tools predict a significant impact on normal splicing by a disruption of ESE sites. At least one publication reports experimental evidence confirming these computational in-silico splicing predictions that this variant results in exon skipping leading to an out of frame fusion of BRCA2 exons 17 and 19 (Fackenthal_2002). This has been additionally corroborated by an HDR assay reporting loss of activity confirming an experimental impact on protein function (Guidugli_2018). The variant was absent in 251098 control chromosomes. c.8165C>G has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Fackenthal_2002, Meisel_2017, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories and one expert panel (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=5 to include the expert panel)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000414368 SCV001446564 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Invitae RCV001193120 SCV001579167 pathogenic Hereditary breast and ovarian cancer syndrome 2020-06-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 2722 of the BRCA2 protein (p.Thr2722Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (rs80359062, ExAC no frequency). This variant has been reported to segregate in affected members of a family with breast and/or ovarian cancer (PMID: 12145750). Experimental studies have shown that this variant disrupts BRCA2 homology-directed repair activity, regulation of centrosome amplification, and complementation of the lethality in BRCA2-deficient mouse embryonic stem cells (PMID: 23108138, 18451181, 25146914, 18607349). Furthermore, this missense change was also shown to lead to a splicing defect that skips exon 18 and is predicted to result in an absent or truncated protein product (PMID: 12145750, 18607349). Based on a multifactorial likelihood algorithm using genetic, functional, and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 24323938, 21990134, 23108138). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000031723 SCV000030148 uncertain significance Breast-ovarian cancer, familial 2 2002-09-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000031723 SCV000054330 pathogenic Breast-ovarian cancer, familial 2 2011-11-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031723 SCV000147286 uncertain significance Breast-ovarian cancer, familial 2 2013-02-20 no assertion criteria provided clinical testing

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