ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3032C>G (p.Thr1011Arg) (rs80358548)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195327 SCV000072118 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-17 criteria provided, single submitter clinical testing
GeneDx RCV000589304 SCV000210302 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3032C>G at the cDNA level, p.Thr1011Arg (T1011R) 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 3260C>G. This variant has been identified in individuals/families with breast and/or ovarian cancer, but one corresponding breast tumor did not show loss of heterozygosity (De Sanjose 2003, Balia 2011, Alsop 2012, Gabald? Barrios 2017). A functional study in a human cell line found that this variant did not increase spontaneous homologous recombination as compared to wild type, leading authors to conclude that it is likely not pathogenic (Balia 2011). However, another functional study in yeast found that BRCA2 Thr1011Arg did not induce any recombination events, a result similar to the pathogenic control (Spugnesi 2013). In addition, this variant demonstrated impaired binding to both APRIN and RAD51 proteins (Brough 2012). BRCA2 Thr1011Arg was observed at an allele frequency of 0.009% (1/11436) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Thr1011Arg occurs at a position that is conserved across species and is located in the BRC1 domain and the RAD51 binding region (Cole 2011, Roy 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Thr1011Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000164588 SCV000215247 likely benign Hereditary cancer-predisposing syndrome 2017-06-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Other data supporting benign classification
Counsyl RCV000031396 SCV000488747 uncertain significance Breast-ovarian cancer, familial 2 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589304 SCV000694660 uncertain significance not provided 2016-11-11 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3032C>G (p.Thr1011Arg) variant located in a BRCA2 repeat domain causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured here due to low reliability) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/120282 (1/40160), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. This variant has been reported in multiple affected individuals without strong evidence of causality. Three individuals (two cited by UMD and one cited by BIC) carrying this variant with co-occurrence of another BRCA1 pathogenic variant, suggesting against pathogenicity of our variant of interest. Functional studies showed inconsistent results, Balia_2011 showed that variant did not increase the spontaneous HR in the tested HelaG1 cell line (as WT) and concluded variant of interest as a likely benign variant. However, Spugnesi_2013 used yeast recombination assay to show that variant of interest did not induce HR (as pathogenic variant controls) and Brough_2012 showed variant fragment of BRCA2 protein with decreased interaction with both APRIN and RAD51 proteins detected via co-IP assay. In addition, multiple clinical diagnostic laboratories/reputable databases cite the variant with conflicting classifications "uncertain significance" or "likely benign." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign."
GeneKor MSA RCV000164588 SCV000821932 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000164588 SCV000910904 likely benign Hereditary cancer-predisposing syndrome 2016-04-18 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031396 SCV000054001 likely benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031396 SCV000146158 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148418 SCV000190117 likely benign Neoplasm of the breast 2014-06-01 no assertion criteria provided research

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