ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5635G>A (p.Glu1879Lys) (rs55996097)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167807 SCV000072715 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129072 SCV000183775 likely benign Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000755862 SCV000210616 likely benign not provided 2020-03-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32426482, 27062684, 28222693, 28263838, 18092194, 24504028, 26689913, 23555315, 20104584, 18627636, 22811390, 16847550, 16760289)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077357 SCV000296630 uncertain significance Breast-ovarian cancer, familial 2 2016-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000336386 SCV000383719 likely benign Fanconi anemia, complementation group D1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000077357 SCV000383720 likely benign Breast-ovarian cancer, familial 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168580 SCV000694886 benign not specified 2020-02-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5635G>A (p.Glu1879Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 248816 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer allowing no conclusion about variant significance. c.5635G>A has been reported in the literature in sequencing studies of individuals affected with Hereditary Breast and Ovarian Cancer, contralateral breast cancer, and other cancerous settings ((example, Borg_2010, Capalbo_2006, Capanu_2011, Cunningham_2014, Giannini_2006, Haiman_2013, Pennington_2013, Seymour_2008, Thirthagiri_2008, Azzolini_2016, Lai_2017, Zuntini_2018). The variant was reported as not co-segregating with disease in at-least one of these reports (Zuntini_2018). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants in the BRCA2 and BRCA1 genes have been reported in the UMD and the BIC databases respectively in addition to another co-occurrence in the MSH6 gene tested at our laboratory (BRCA2 c.8463dup, p.Ile2822fs; BRCA1 c.5263_5264insC, p.Ser1755?fs, MSH6 c.3733_3739dupTTTTCAA , p.Thr1247fsX30), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Some of these submitters cite overlapping evidence utilized in the context of this evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=6). Based on the evidence outlined above, the variant was re-classified from likely benign to benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077357 SCV000744471 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755862 SCV000883488 likely benign not provided 2017-09-06 criteria provided, single submitter clinical testing The p.Glu1879Lys variant has been reported in individuals with breast and/or ovarian cancer; however, inheritance and specific clinical information were not reported (Borg 2010, Pennington 2012, and Thirthagiri 2008). The p.Glu1879Lys variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.023% in the South Asian population (identified in 7 out of 29,948 chromosomes; 1 homozygote), and is classified as likely benign/benign in ClinVar (Variant ID: 51895). The glutamic acid at codon 1,879 is moderately conserved considering 12 species (Alamut software v2.9.0), and it is a lysine in dogs, suggesting that this change may be evolutionary tolerated. Computational analyses predict that this variant does not affect the BRCA2 protein structure/function (GV/GD: C0, SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). Based on the available evidence, the p.Glu1879Lys variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000755862 SCV000887853 likely benign not provided 2020-02-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129072 SCV000902758 benign Hereditary cancer-predisposing syndrome 2016-09-08 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646418 SCV001854846 likely 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) RCV000077357 SCV000109154 benign Breast-ovarian cancer, familial 2 2009-08-24 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077357 SCV000146649 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 RCV000077357 SCV000733268 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000077357 SCV001553809 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Glu1879Lys variant was identified in 3 of 4882 proband chromosomes (frequency: 0.0006) from Malaysian and American individuals or families with breast or endometrial cancer (Thirthagiri 2008, Pennington 2012, Borg 2010). The variant was also identified in dbSNP (ID: rs55996097) “With Pathogenic, other allele”, ClinVar (conflicting interpretations of pathogenicity: classified as benign by Invitae and SCRP; classified as likely benign by Ambry Genetics, GeneDx, Illumina Clinical Services Laboratory, and two other clinical laboratories; and classified as uncertain significance by BIC, Integrated Genetics/Laboratory Corporation of America, CHEO and Quest Diagnostics Nichols Institute San Juan Capistrano), GeneInsight-COGR (1x), LOVD 3.0 (1x), UMD-LSDB (classified as 3-UV, co-occurring with the pathogenic variant BRCA2 c.8643dup, p.Ile2822Tyrfs*23) and BIC Database (10x, clinical importance unknown, classification pending). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 35 of 274724 chromosomes (1 homozygous) at a frequency of 0.0001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 28 of 125750 chromosomes (freq: 0.0002), and South Asian in 7 (1 homozygous) of 29948 chromosomes (freq: 0.0002), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Glu1879 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
Human Genetics - Radboudumc,Radboudumc RCV000755862 SCV001954563 likely benign not provided no assertion criteria provided clinical testing

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