ClinVar Miner

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

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Total submissions: 12
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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 The p.D2723G pathogenic mutation (also known as c.8168A>G), located in coding exon 17 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8168. This alteration was shown to create an aberrant splice product (Walker LC et al. Hum. Mutat. 2010 Jun;31(6):E1484-505; Sanz DJ et al. Clin Cancer Res. 2010 Mar 15;16(6):1957-67; Thery JC et al. Eur J Hum Genet. 2011 Oct;19(10):1052-8; Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38). In addition, in-vitro functional studies demonstrated reduced homologous recombination and increased centrosome amplification (Farrugia DJ et al. Cancer Res. 2008 May 1;68(9):3523-31; Walker LC et al. Hum. Mutat. 2010 Jun;31(6):E1484-505). Furthermore, this alteration could not complement the lethality of BRCA2-deficient mouse-embryonic stem (mES) cells (Hendriks G et al. Hum. Mutat. 2014 Nov;35(11):1382-91). This alteration has been classified as a pathogenic mutation based on a posterior probability model, which integrates evolutionary conservation and multifactorial analysis (including segregation, co-occurrence, family history, and tumor histology) (Easton D et al. Am J Hum Genet. 2007;81:873-883; Lindor NM et al. Hum. Mutat. 2012 Jan;33(1):8-21). Three other alterations have also been reported at the same codon, at least one of which (p.D2723H) is a well-described pathogenic mutation (Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8). Based on the available evidence, this alteration is classified as a pathogenic mutation.
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 2019-10-22 criteria provided, single submitter clinical testing Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
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 Health, Inc RCV000131682 SCV000689102 pathogenic Hereditary cancer-predisposing syndrome 2021-02-15 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 2723 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). Functional RNA studies have shown that this variant causes exon 18 skipping or partial exon 18 deletion, resulting in premature truncation (PMID: 20215541, 20513136, 21673748). Functional studies have shown that this variant resulted in impaired DNA repair in cell culture (PMID: 18451181, 20513136, 29394989) or failure to complement BRCA2-deficient mouse cells. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 17924331, 20513136, 24052750, 25452441, 29088781, 29335924). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.
Counsyl RCV000031724 SCV000785661 pathogenic Breast-ovarian cancer, familial 2 2017-10-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Invitae RCV000781040 SCV001585115 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 2723 of the BRCA2 protein (p.Asp2723Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 25452441), and an individual undergoing genetic testing (PMID: 27886673). ClinVar contains an entry for this variant (Variation ID: 38141). Experimental RNA studies have shown that this sequence change results in a less abundant aberrantly spliced transcript that creates a truncated product, and in a full length transcript (PMID: 21673748, 22505045, 28339459). The full-length protein product containing this missense change was shown to result in increased centrosome amplification and reduced homologous recombination activity indicating disruption of BRCA2 protein function (PMID: 20513136, 18451181, 25146914). In addition, based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID:17924331, 21990134, 24323938). A different missense substitution at this codon (p.Asp2723His) has been determined to be pathogenic (PMID: 15290653, 16489001, 15695382, 18607349, 24013206). This suggests that the aspartic acid residue is critical for BRCA2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been 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
CZECANCA consortium RCV001271062 SCV001451884 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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