ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8243G>A (p.Gly2748Asp) (rs80359071)

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Total submissions: 15
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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) RCV000113895 SCV000244484 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
Invitae RCV000045460 SCV000073473 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 2748 of the BRCA2 protein (p.Gly2748Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (rs80359071, ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 15026808, 17924331, 22711857). ClinVar contains an entry for this variant (Variation ID: 52535). Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). Experimental studies have shown that this missense change disrupts homology directed recombination and the regulation of centrosome amplification (PMID: 18451181, 21671020, 23108138, 23328489, 25146914). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000216216 SCV000274383 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-08 criteria provided, single submitter clinical testing The p.G2748D variant (also known as c.8243G>A), located in coding exon 17 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8243. The glycine at codon 2748 is replaced by aspartic acid, an amino acid with very few similar properties. This alteration, also referred to as 8471G>A in some literature, has been shown to have decreased homologous repair activity in multiple assays and to be functionally deficient in a BRCA2-null mouse embryonic stem cell complementation assay (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Hum. Mutat. 2014 Feb;35:151-64; Guidugli L et al. Am J Hum Genet. 2018 Feb 1;102(2):233-248; Mesman RLS et al. Genet Med. 2018 Jul 10). This alteration was classified as pathogenic based on the likelihood ratio of protein loss of function calculated by bioinformatics integration of protein sequence, conservation, and structure (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481847 SCV000296703 pathogenic not provided 2020-07-11 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because there are too few occurrences in population data. 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. 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 RCV000113895 SCV000327843 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000481847 SCV000568124 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.8243G>A at the cDNA level, p.Gly2748Asp (G2748D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). Using alternate nomenclature, this variant has been previously published as BRCA2 8471G>A. This variant has been observed in multiple families with Hereditary Breast and Ovarian Cancer (Claes 2004, Easton 2007, Farrugia 2008, Lee 2014, Lin 2016). The variant was strongly predicted by Easton et al. (2007) and Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with pathogenic variants. Homologous recombination assays, centrosome amplification analysis, and complementation studies are consistent with BRCA2 Gly2748Asp having a pathogenic effect (Farrugia 2008, Balia 2011, Guidugli 2013, Spugnesi 2013, Hendriks 2014). BRCA2 Gly2748Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gly2748Asp is located within a DSS1 contacting residue of the DNA binding domain (Yang 2002). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, we consider this variant to be pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000045460 SCV000605806 pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-21 criteria provided, single submitter clinical testing The p.Gly2748Asp variant in BRCA2 has been reported in at least 10 individuals w ith BRCA2-associated cancers (Claes 2014, Breast Cancer Information Core (BIC) d atabase), and it was absent from large population studies. In vitro functional s tudies provide some evidence that the p.Gly2748Asp variant may impact protein fu nction (Guidugli 2014, Spugnesi 2013). In addition, this variant was classified as Pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (Cl inVar SCV000244484.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Counsyl RCV000113895 SCV000677699 pathogenic Breast-ovarian cancer, familial 2 2016-11-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000216216 SCV000689109 pathogenic Hereditary cancer-predisposing syndrome 2020-03-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045460 SCV000695136 pathogenic Hereditary breast and ovarian cancer syndrome 2021-05-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8243G>A (p.Gly2748Asp) results in a non-conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 252586 control chromosomes. c.8243G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and pancreatic cancer (example, Li_2018, Hu_2018, Lin_2016, Alsop_2012 and Claes_2004, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Multiple independent functional studies demonstrated a deleterious impact by the variant resulting in impaired homologous recombination activity of BRCA2 and inability to complement the loss of cell viability in mouse embryonic stem cell-based functional assays, further supporting a disease-causing impact (Guidugli_2018, Mesman_2018, Hendriks_2014, Guidugli_2012, and Farrugia_2009). Multiple clinical diagnostic laboratories, a consortium (CIMBA) and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000045460 SCV000838871 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000113895 SCV000839922 pathogenic Breast-ovarian cancer, familial 2 2018-03-05 criteria provided, single submitter clinical testing This c.8243G>A (p.Gly2748Asp) variant in the BRCA2 gene has been reported in multiple breast cancer and ovarian cancer patients [PMID 15026808, 22711857] while only observed with extremely low allele frequency in general population according to gnomad database. Glycine at amino acid position 2748 is highly conserved during evolution. Functional studies showed that this mutant causes reduced homology-directed recombination repair activity, compared to wild type [PMID:18451181, 23328489, 25146914]. Multiple in silico predictions suggest this glycine to asparatic acid change is deleterious. Based upon above evidences, this c.8243G>A (p.Gly2748Asp) variant in the BRCA2 gene is classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113895 SCV000147307 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113895 SCV000297564 pathogenic Breast-ovarian cancer, familial 2 2010-04-26 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000481847 SCV000592180 likely pathogenic not provided no assertion criteria provided clinical testing The p.Gly2748Asp variant has been reported in the literature in 3/3590 proband chromosomes of individuals with hereditary breast and ovarian cancer and ovarian carcinoma, although no control chromosomes were tested to establish the frequency in the general population (Alsop 2012, Balia 2011, Claes 2004, Farrugia 2008, Karchin 2008, Lindor 2012, Easton 2007). The p.Gly2748 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM) suggest that the p.Gly2748Asp variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant is listed in the dbSNP database (ID#:rs80359071) as coming from a "clinical source" but no frequency information was provided, and so the prevalence of this variant in the population is not known. In a study that interrogated the Myriad Genetic Laboratories database to assess the clinical significance of BRCA1/2 sequence variants, segregation studies and statistical analyses suggested the p.G2748D variant was in “favour of causality” (Easton 2007). In addition, functional studies have shown that the homologous recombination repair activity is compromised, as determined by transient overexpression of this variant protein, and that it leads to an increase in the proportion of cells undergoing aberrant centriole amplification (Balia 2011, Farrugia 2008). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as Predicted Pathogenic.

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