ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6953G>A (p.Arg2318Gln) (rs80358921)

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Total submissions: 13
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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) RCV000077390 SCV001161528 benign Breast-ovarian cancer, familial 2 2019-06-18 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 = 0.000238
Invitae RCV001086727 SCV000073109 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131677 SCV000186713 likely benign Hereditary cancer-predisposing syndrome 2018-06-27 criteria provided, single submitter clinical testing Other data supporting benign classification
GeneDx RCV000656799 SCV000210409 likely benign not provided 2019-09-05 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10923033, 21702907, 25452441, 17972171, 25348012, 27153395, 21990134, 16489001, 21990165, 21741379, 22711857, 26941049, 21952622, 25479140, 31131967)
Department of Pathology and Molecular Medicine,Queen's University RCV000168594 SCV000588112 likely benign not specified 2017-04-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131677 SCV000903879 likely benign Hereditary cancer-predisposing syndrome 2016-05-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656799 SCV001133882 uncertain significance not provided 2019-05-07 criteria provided, single submitter clinical testing
Mendelics RCV000077390 SCV001139164 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646598 SCV001854903 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) RCV000077390 SCV000109187 likely benign Breast-ovarian cancer, familial 2 2012-03-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077390 SCV000146980 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735593 SCV000863731 uncertain significance Breast and/or ovarian cancer no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354760 SCV001549452 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Arg2318Gln variant was identified in 5 of 12202 proband chromosomes (frequency: 0.0004) from individuals or families with breast, ovarian, prostate, and pancreatic cancer and was not identified in 360 control chromosomes from healthy individuals (Alsop_2012, Kote-Jarai_2011, Couch_2015, Dos Santos Vidal_2016, Grant_2015, Chenevix-Trench_2006). The variant was also identified in the following databases: dbSNP (ID: rs80358921) as “With other allele”, ClinVar and Clinvitae (6x as likely benign by Ambry Genetics, COGR, Invitae, SCRP and as uncertain significance by GeneDx, BIC), LOVD 3.0 (5x), UMD-LSDB (5 entries as uncertain significance and in one case the p.Arg2318Gln variant has been reported as co-occurring with a pathogenic variant of BRCA2 gene (c.2330dup, p.Asp777GlnfsX11), BIC Database (4x), ARUP Laboratories (1x as “class 2-likely not pathogenic or of little clinical significance”). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Database. The variant was identified in control databases in 2 of 244730 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 33426 chromosomes (freq: 0.00003), European Non-Finnish in 1 of 111204 chromosomes (freq: 0.000009); but not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. A functional study showed decreased cell survival and a higher rate of apoptosis in response to cisplatin as compared to wild-type (Warren_2011). The p.Arg2318 residue is not 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 very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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. This variant is classified as a variant of uncertain significance.

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