ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9875C>T (p.Pro3292Leu) (rs56121817)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000513762 SCV000885091 uncertain significance not provided 2017-11-14 criteria provided, single submitter clinical testing The BRCA2 c.9875C>T; p.Pro3292Leu variant is described in the medical literature in individuals and families with breast cancer (Borg 2010, Francies 2015, Riahi 2015, Chao2016). However, the variant was also published in an individual with Fanconi anemia who also carried two nonsense variants in the FANCC gene (Nicchia 2015). The variant is listed in the ClinVar database as both a variant of uncertain significance and as likely benign/benign (Variation ID: 52910). The variant is listed in the dbSNP variant database (rs56121817) and in the Genome Aggregation Database in 20/245936 alleles. The proline at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. While in silico studies imply this variant may impact function (Tram 2013) functional studies show that this variant has no effect on at least some functions (Eashi 2005, Hucl 2008). Considering available information, this variant cannot be classified with certainty. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Chao A et al. Prevalence and clinical significance of BRCA1/2 germline and somatic mutations in Taiwanese patients with ovarian cancer. Oncotarget. 2016 Dec 20;7(51):85529-85541. Esashi F et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature. 2005 Mar 31;434(7033):598-604. Francies FZ et al. BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer. BMC Cancer. 2015 Nov 17;15:912. Hucl T et al. A syngeneic variance library for functional annotation of human variation: application to BRCA2. Cancer Res. 2008 Jul 1;68(13):5023-30. Nicchia E et al. Identification of point mutations and large intragenic deletions in Fanconi anemia using next-generation sequencing technology. Mol Genet Genomic Med. 2015 Jul 2;3(6):500-12. Riahi A et al. Mutation spectrum and prevalence of BRCA1 and BRCA2 genes in patients with familial and early-onset breast/ovarian cancer from Tunisia. Clin Genet. 2015 Feb;87(2):155-60. Tram E et al. Missense variants of uncertain significance (VUS) altering the phosphorylation patterns of BRCA1 and BRCA2. PLoS One. 2013 May 21;8(5):e62468.
Ambry Genetics RCV000131346 SCV000186321 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-29 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,Insufficient evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077478 SCV000145724 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000513762 SCV000610403 uncertain significance not provided 2017-03-29 criteria provided, single submitter clinical testing
Color RCV000131346 SCV000902771 benign Hereditary cancer-predisposing syndrome 2016-05-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000513762 SCV000228418 uncertain significance not provided 2014-12-23 criteria provided, single submitter clinical testing
GeneDx RCV000045908 SCV000210519 likely benign not specified 2018-02-21 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.
Illumina Clinical Services Laboratory,Illumina RCV000195340 SCV000383806 likely benign Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000301085 SCV000383807 likely benign Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000513762 SCV000695277 likely benign not provided 2016-02-08 criteria provided, single submitter clinical testing Variant summary: This c.9875C>T variant affects a conserved nucleotide and results in a replacement of a Proline (P) with a Leucine (L). Both amino acid residues are medium size and hydrophobic therefore this substitution likely does not alter the physio-chemical properties of the protein. 5/5 in silico tools predict a damaging outcome for this variant; however they are not definitive. It was observed in the large and broad cohorts of the ExAc project at an allele frequency of 0.0074% (9/121354 chromosomes) which does not exceed the maximal expected allele frequency of a disease causing BRCA2 allele (0.075%) to exclude pathogenicity. However, the variant could still represent as a rare polymorphism unless proven otherwise. In literature, this variant has been reported in multiple breast/or ovarian cancer patients (Borg _2010; Capanu _2011, Riahi _2013); however information about co-segregation and/or co-occurrence was not provided. Therefore available clinical data do not support for a cause-effect relationship between the variant and HBOC. Functional studies reported the variant is capable of binding to RAD51; supports RAD51 foci formation and facilitates the DNA repair (Esashi _2005, Hucl _2008). These functional assay results support for a benign outcome. Furthermore, SCRP reports co-occurrence with a likely pathogenic BRCA2 variant 9502delT in one individual and classifies variant as Likely Benign. BIC also reports the variants co-occurrence with p.E1308X in one sample. Clinical labs have classified this variant either as uncertain significance (n=4) or as likely benign (n=2). Taken together, mainly based on its occurrence in general population and its co-occurrence with deleterious variants, this variant has currently been classified as likely benign.
Invitae RCV000195340 SCV000073921 benign Hereditary breast and ovarian cancer syndrome 2017-12-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000045908 SCV000538504 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Br.Ca. patient, functional study shows potential impact (not enough to go above VUS); ClinVar: 4 VUS, 2 LB
Mendelics RCV000195340 SCV000838912 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000077478 SCV000267833 likely benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077478 SCV000296514 uncertain significance Breast-ovarian cancer, familial 2 2016-05-13 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077478 SCV000109276 likely benign Breast-ovarian cancer, familial 2 2008-06-05 no assertion criteria provided clinical testing

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