ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9285C>G (p.Asp3095Glu) (rs80359198)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045779 SCV000073792 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 3095 of the BRCA2 protein (p.Asp3095Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (no ExAC frequency). This variant has been reported in many families with supportive evidence of segregation with a BRCA2-related disease (PMID: 18451181, 18951446, 22678057). It is also known as 9513C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 52805). Experimental studies have shown that this variant disrupts BRCA2 homology directed repair activity, and suppresses the ability of BRCA2 to restore viability to BRCA2-null mouse embryonic stem cells (PMID: 22678057, 23108138, 18451181). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a very high probability of being pathogenic (PMID: 17924331, 21990134, 22678057). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000223197 SCV000276898 pathogenic Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
GeneDx RCV000236007 SCV000292530 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9285C>G at the cDNA level, p.Asp3095Glu (D3095E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). Also published as BRCA2 9513C>G using alternate nomenclature, this variant has been observed in an individual with personal and family history of breast/ovarian cancer as well as in two individuals with male breast cancer (Plon 2008, Gabald? Barrios 2017). This variant has exhibited reduced homology-directed repair (HDR) activity, aberrant centriole amplification and failure to rescue the lethality of Brca2 null ES cells, all suggestive of pathogenicity (Farrugui 2008, Biswas 2012, Guidugli 2012). Various multifactorial models have strongly predicted this variant to be pathogenic, based on clinical histories, family studies, co-occurrence with deleterious variants, tumor histopathology, and other factors (Easton 2007, Lindor 2012, Vallee 2012). BRCA2 Asp3095Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236007 SCV000600853 likely pathogenic not provided 2016-10-24 criteria provided, single submitter clinical testing
Color RCV000223197 SCV000684048 pathogenic Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045779 SCV000695233 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9285C>G (p.Asp3095Glu) results in a conservative amino acid change located in the oligonucleotide/oligosaccharide-binding, domain 3 of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245472 control chromosomes. c.9285C>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. The variant has been reportedly identified in at least 27 HBOC families (Maillet _2006, Biswas_2012, Gabaldo_2018) with segregation data suggestive, but not conclusive of causality. Several publications report experimental evidence evaluating an impact on protein function. In the functional studies the variant was shown to cause significantly reduced HDR activity and increased aberrant centriole amplification, both suggestive of a deleterious impact (Guidugli-2012, Biswas_2012, Farrugia_2008). Multiple multifactorial algorithms favor pathogenicity (Easton_2007, Lindor_2012, Guidugli_2018). 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077467 SCV000109265 pathogenic Breast-ovarian cancer, familial 2 2010-03-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077467 SCV000147600 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045779 SCV000587995 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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