ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.467A>G (p.Asp156Gly) (rs68071147)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167806 SCV000072481 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129132 SCV000183850 likely benign Hereditary cancer-predisposing syndrome 2018-05-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
GeneDx RCV000044468 SCV000210243 likely benign not specified 2017-09-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Pathway Genomics RCV000077333 SCV000223762 uncertain significance Breast-ovarian cancer, familial 2 2014-10-30 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000167806 SCV000267841 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-04-25 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000044468 SCV000588067 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001281728 SCV000600601 uncertain significance not provided 2020-02-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044468 SCV000694795 uncertain significance not specified 2021-05-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.467A>G (p.Asp156Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, several computational tools predict a significant impact on normal splicing: 4 predict the variant creates a cryptic exonic 5' donor site, 9 nucleotides upstream from the canonical splice site. These predictions were confirmed by ex vivo studies (using patient derived lymphocyte mRNA) and in vitro functional assays (testing the variant in minigene assays); all demonstrating that the variant results in a 9 nucleotides deletion (r.467_475del) in the majority of the transcripts, which would result in an in-frame deletion of 3 amino acids (p.D156_S158del) at the protein level (Houdayer_2012, Sanz_2010, Fraile-Bethencourt_2019). Another in vitro study, examining the effect of this variant at the protein level using an (intronless) cDNA construct, demonstrated that the Asp156Gly missense variant does not affect the HDR function of BRCA2 in a PARP-inhibitor sensitivity assay (Ikegami_2020), however, in light of the strong spliceogenic effect, this finding might not reflect the overall protein level effect of the variant. The variant allele was found at a frequency of 7.2e-05 in 251690 control chromosomes, predominantly observed within the African or African-American subpopulation at a frequency of 0.00056 (i.e. 14/24866 alleles) in the gnomAD database. This frequency is slightly lower than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00056 vs 0.00075), therefore these data do not allow clear conclusions about the variant. The variant, c.467A>G, has been reported in the literature in at least 3 individuals with personal and/or family history of Hereditary Breast and Ovarian Cancer (Suter_2004, Borg_2010, Houdayer_2012), though it was also found in 2 women, older than age 70 years, who have never had cancer (in FLOSSIES database, containing approximately 10,000 women). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=4; VUS, n=5). At-least one submitters reporting a likely benign outcome mentions a possible co-occurrence, although it is not explicitly specified. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional conclusive evidence supporting a neutral outcome are identified.
Color Health, Inc RCV000129132 SCV000903073 likely benign Hereditary cancer-predisposing syndrome 2016-04-21 criteria provided, single submitter clinical testing
Mendelics RCV000077333 SCV001138962 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000044468 SCV001157833 uncertain significance not specified 2018-08-27 criteria provided, single submitter clinical testing The BRCA2 c.467A>G; p.Asp156Gly variant (rs68071147) is reported in the literature in several individuals affected with breast and/or ovarian cancer (Capanu 2011, Sanz 2010, Suter 2004). This variant is reported in ClinVar (Variation ID: 51694) and is found in the African population with an overall allele frequency of 0.05% (13/24012 alleles) in the Genome Aggregation Database. The aspartate at codon 156 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Analyses of splicing (Alamut v.2.11) predict that this variant creates a novel cryptic splice donor site, and mRNA studies indicate that splicing occurs at this cryptic site, resulting in an in-frame deletion of 9 nucleotides at the end of exon 5 (Houdayer 2012, Sanz 2010). However, due to limited information on the clinical impact of the p.Asp156Gly variant, its significance is uncertain at this time. References: Capanu M et al. Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. Genet Epidemiol. 2011 Jul;35(5):389-97. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. Sanz DJ et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67. Suter NM et al. BRCA1 and BRCA2 mutations in women from Shanghai China. Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):181-9.
Sharing Clinical Reports Project (SCRP) RCV000077333 SCV000109130 uncertain significance Breast-ovarian cancer, familial 2 2007-07-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077333 SCV000146918 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 RCV000044468 SCV000587549 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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