ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8168A>G (p.Asp2723Gly) (rs41293513)

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Total submissions: 10
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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) RCV000031724 SCV000244482 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 RCV000131682 SCV000186718 pathogenic Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing Other strong data supporting pathogenic classification;Well-characterized mutation at same position;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000216099 SCV000279418 pathogenic not provided 2016-02-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.8168A>G at the cDNA level, p.Asp2723Gly (D2723G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). Using alternate nomenclature, this variant has been previously published as BRCA2 8396A>G. This variant has been identified in at least one individual with triple negative breast cancer (Couch 2015). Protein, RNA, and minigene assays have demonstrated that this variant creates a cryptic splice donor site that when utilized, leads to a shortened protein product (Sanz 2010, Walker 2010, Théry 2011). When present in the full-length transcript, BRCA2 Asp2723Gly causes defective homologous recombination, centrosome amplification, and defective cell growth following DNA damage (Farrugia 2008, Walker 2010, Hendriks 2014). This 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 variants.BRCA2 Asp2723Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp2723Gly occurs at a position that is conserved across species and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216099 SCV000296627 pathogenic not provided 2015-08-25 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031724 SCV000327826 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000131682 SCV000689102 pathogenic Hereditary cancer-predisposing syndrome 2017-09-01 criteria provided, single submitter clinical testing
Counsyl RCV000031724 SCV000785661 pathogenic Breast-ovarian cancer, familial 2 2017-10-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781040 SCV000918812 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8168A>G (p.Asp2723Gly) variant involves the alteration of a highly conserved nucleotide leading to a missense change in the DNA-binding domain (IPR012340) in the OB1 (oligonucleotide binding) fold (IPR015187, InterPro). Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools also predict a significant impact on normal splicing: four predict the variant creates a cryptic 5 donor splice site. These predictions are corroborated by publications reporting experimental evidence that this variant affects mRNA splicing (Walker 2010, Rodriguez-Balada 2016, Sanz 2010), partly generating an aberrantly spliced transcript encoding a truncated protein, but in part the variant allele becomes also transcribed to a full length transcript encoding a missense protein that was reported to have a reduced function (Farrugia 2008, Walker 2010). The most pronounced variant effect results in 10%-<30% of normal activity. The variant was absent in 247432 control chromosomes. The variant c.8168A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Walker 2010, Couch 2015, Rodriguez-Balada 2016, Alvarez 2017, Farrugia 2008). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031724 SCV000054331 pathogenic Breast-ovarian cancer, familial 2 2013-10-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031724 SCV000147289 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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