ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8525G>A (p.Arg2842His) (rs80359105)

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Total submissions: 17
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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) RCV000077444 SCV000244486 benign 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 1 based on posterior probability = 0.000259
Invitae RCV001084291 SCV000073558 benign Hereditary breast and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000587725 SCV000210671 likely benign not provided 2020-11-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17924331, 21990134, 24323938, 21218378, 19043619, 20167696, 28624499, 11304778, 26757417, 18284688, 14520696, 25348012, 16683254, 28324225, 18951446, 29394989, 30093976, 32444794, 29884841)
Ambry Genetics RCV000163013 SCV000213501 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000077444 SCV000487766 benign Breast-ovarian cancer, familial 2 2015-12-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163013 SCV000537493 likely benign Hereditary cancer-predisposing syndrome 2020-03-13 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000045545 SCV000588120 benign not specified 2017-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587725 SCV000695163 likely benign not provided 2016-04-08 criteria provided, single submitter clinical testing Variant summary: The c.8525G>A variant affects a conserved nucleotide, resulting in amino acid change from Arg to His. 5/5 in-silico tools predict damaging outcome for this variant; however, they are not definitive. This variant is found in 7/121316 control chromosomes predominantly in East Asian population with an allele frequency of 0.00057 (5/8634 chromosomes) which does not exceed the maximal expected frequency of a pathogenic allele (0.0007503) in this gene. However, the frequency data may still suggest that this variant is a rare polymorphism. The variant has been reported in multiple HBOC patients/families without strong evidence for causality. More importantly, the variant has been reported to co-occur with truncating variants in BRCA1/2, namely BRCA1 p.Glu879Ter and BRCA2 p.Gln3066Ter, strongly suggesting for benign outcome. Multifactorial probability based models also strongly suggest for a benign outcome. Multiple clinical labs and reputable databases have classified this variant as benign/likely benign. Taken together, this variant has been classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000077444 SCV000743348 likely benign Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077444 SCV000744541 benign Breast-ovarian cancer, familial 2 2017-05-31 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646806 SCV001852800 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077444 SCV000109242 benign Breast-ovarian cancer, familial 2 2010-10-07 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077444 SCV000147391 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077444 SCV000733318 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358481 SCV001554226 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Arg2842His variant was identified in 5 of 3552 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Chao 2016, Lee 2008, Martin 2001, Ng 2016). The variant was also identified in dbSNP (ID: rs80359105 as With Uncertain significance, other allele), ClinVar (13x as benign or likely benign, reviewed by an expert panel), LOVD 3.0 (17x between benign and inconclusive), UMD-LSDB (1 x as likely neutral), and ARUP Laboratories (as not pathogenic). The variant was not identified in Cosmic, MutDB, BIC Database, or Zhejiang University Database. The variant was identified in control databases in 16 of 276812 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), Latino in 1 of 34416 chromosomes (freq: 0.00003), European Non-Finnish in 6 of 126350 chromosomes (freq: 0.00005), and East Asian in 8 of 18852 chromosomes (freq: 0.0004); it was not observed in the “Other”, Ashkenazi Jewish, Finnish, and South Asian populations. One study showed homology-directed DNA repair activity by the p.Arg2842His variant (Guidugli 2018) and mathematical models predict that this variant is benign (Easton 2007, Lindor 2012). The p.Arg2842 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not reliably predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although the information currently available suggests a benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000045545 SCV001906170 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000045545 SCV001953199 benign not specified no assertion criteria provided clinical testing

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