ClinVar Miner

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

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Total submissions: 11
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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 Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
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 RCV000163026 SCV000689101 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000414368 SCV000887932 pathogenic not provided 2017-09-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
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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