ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.831T>G (p.Asn277Lys) (rs28897705)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082295 SCV000073484 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130334 SCV000185184 likely benign Hereditary cancer-predisposing syndrome 2018-06-25 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting benign classification
Michigan Medical Genetics Laboratories,University of Michigan RCV000031735 SCV000195953 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000045471 SCV000210256 likely benign not specified 2017-11-01 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000045471 SCV000538502 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: 1 report identified this varint in a prostate cancer cohort - reported as unclassified variant; ClinVar: 3 VUS, 2 LB/B
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586134 SCV000695142 likely benign not provided 2017-07-10 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031735 SCV000743251 likely benign Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031735 SCV000744394 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769681 SCV000901094 uncertain significance Breast and/or ovarian cancer 2017-02-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130334 SCV000910741 likely benign Hereditary cancer-predisposing syndrome 2016-01-13 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586134 SCV001148970 likely pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586134 SCV001469460 uncertain significance not provided 2019-11-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289664 SCV001477630 uncertain significance none provided 2020-06-15 criteria provided, single submitter clinical testing The BRCA2 c.831T>G; p.Asn277Lys variant (rs28897705) is reported in the literature in individuals affected with breast, ovarian, prostate, or pancreatic cancer, although it was not demonstrated to be disease-causing (Kote-Jarai 2011, Schubert 2017, Schwartz 2019, van der Hout 2006). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (19/127296 alleles) in the Genome Aggregation Database. The asparagine at codon 277 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with predictions, one study observed the p.Asn277Lys variant disrupted interactions with factors involved with cytokinesis, and its expression in cultured cells correlated with a higher percentage of multinucleate cells (Mondal 2012), although the clinical significance of these observations has not been demonstrated. Due to limited information, the clinical significance of the p.Asn277Lys variant is uncertain at this time. References: Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011;105(8):1230-1234. Mondal G et al. BRCA2 localization to the midbody by filamin A regulates cep55 signaling and completion of cytokinesis. Dev Cell. 2012;23(1):137-152. Schubert S et al. GT198 (PSMC3IP) germline variants in early-onset breast cancer patients from hereditary breast and ovarian cancer families. Genes Cancer. 2017;8(1-2):472-483. Schwartz M et al. Familial pancreatic adenocarcinoma: A retrospective analysis of germline genetic testing in a French multicentre cohort. Clin Genet. 2019;96(6):579-584. van der Hout AH et al. A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. Hum Mutat. 2006;27(7):654-666.
Sharing Clinical Reports Project (SCRP) RCV000031735 SCV000054342 benign Breast-ovarian cancer, familial 2 2009-06-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031735 SCV000145776 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353723 SCV000591715 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asn277Lys variant was identified in 1 of 8048 proband chromosomes (frequency: 0.0001) from individuals or families with breast and ovarian cancer (van der Hout 2006). The variant was also identified in the following databases: dbSNP (ID: rs28897705) as With other allele, ClinVar (conflicting interpretations of pathogenicity), Clinvitae (conflicting interpretations of pathogenicity), COGR (uncertain significance), MutDB, LOVD 3.0 (26X), UMD-LSDB (16X likely neutral), BIC Database (12X unknown significance). The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang Colon Cancer Databases. In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.5909C>A (p.Ser1970X)), increasing the likelihood that the p.Asn277Lys variant does not have clinical significance. In addition, the variant was identified with a co-occurring pathogenic BRCA2 variant (c.4042delT (p.Cys1348ValfsX26)) in on individual from our laboratory, increasing the likelihood that the p.Asn277Lys variant does not have clinical significance. The variant was identified in control databases in 18 of 271412 chromosomes at a frequency of 0.000066 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The functional study by Mondal (2012) suggested that the variant protein disrupted protein interactions, resulting in cytokinetic defects, but had no effect on BRCA2-dependent homologous recombination. The p.Asn277 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031735 SCV000733218 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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