ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9275A>G (p.Tyr3092Cys) (rs80359195)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084297 SCV000073787 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131684 SCV000186720 likely benign Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s)
Counsyl RCV000077466 SCV000221030 likely benign Breast-ovarian cancer, familial 2 2015-01-15 criteria provided, single submitter literature only
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000077466 SCV000267234 uncertain significance Breast-ovarian cancer, familial 2 2016-03-18 criteria provided, single submitter reference population
GeneDx RCV000424310 SCV000512396 likely benign not specified 2017-08-21 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000424310 SCV000602842 likely benign not specified 2019-05-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131684 SCV000684046 likely benign Hereditary cancer-predisposing syndrome 2016-09-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000424310 SCV000695231 likely benign not specified 2020-09-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9275A>G (p.Tyr3092Cys) results in a non-conservative amino acid change located in the OB3 domain (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250758 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8e-05 vs 0.00075), allowing no conclusion about variant significance. c.9275A>G has been reported in the literature in individuals affected with or suspected of Hereditary Breast And Ovarian Cancer Syndrome (examples- Lee_2008, Caux-Moncoutier_2009, Juwle_2012, Peixoto_2014, Kowalik_2018, Santonocito_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function. These studies reported no impact on splicing and normal HDR activity (examples-Caux-Moncoutier_2009, Houdayer_2012, Guidugli_2012). 11 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/ likely benign, n=8; uncertain significance, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000077466 SCV000743363 uncertain significance Breast-ovarian cancer, familial 2 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077466 SCV000744561 uncertain significance Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586462 SCV001133973 likely benign not provided 2020-03-16 criteria provided, single submitter clinical testing
Mendelics RCV000077466 SCV001139255 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077466 SCV000109264 likely benign Breast-ovarian cancer, familial 2 2012-06-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077466 SCV000147597 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000586462 SCV000592272 likely benign not provided no assertion criteria provided clinical testing  The BRCA2 p.Tyr3092Cys variant was identified in 3 of 7064 proband chromosomes (frequency: 0.0004) from Portugese, French and American individuals or families with (hereditary) breast and ovarian cancer (Peixoto 2015, Lee 2008 , Malone 2000, Caux-Moncoutier 2011). Functional assays looking at allelic imbalance, homologous directed DNA repair (HDR) and splicing of the variant did not show any defects and the variant was classified as likely not pathogenic (Caux-Moncoutier 2009, Guidugli 2013, Houdayer 2012). In silico models (protein likelihood ratio and multifactorial probability) also classify the variant as neutral/likely benign (Karchin 2008, Lindor 2012, Easton 2007). The variant is reported in ClinVar (Conflicting interpretations of pathogenicity. Benign by Mendelics in 2019. Likely benign by Counsyl in 2015, Integrated Genetics in 2017, GeneDx in 2017, Invitae in 2019, ARUP Laboratories in 2019, Quest Diagnostics in 2019, Ambry in 2018, Color in 2016, SCRP in 2012, Foulkes Cancer Genetics LDI in 2010. Uncertain significance by BIC in 2004, Erasmus Medical Unit in 2015, PLM at Sinai Health System in 2015, Genome Diagnostics Laboratory at Utrecht Universitiy Medical Cenre in 2014, Soonchunhyang University Bucheon Hospital in 2016), LOVD 2.0 (20 entries, 16x VUS, 1x LB, 1x B), ARUP laboratories (2 - Likely not pathogenic or of little clinical significance) databases. The variant was identified in dbSNP (rs80359195) as Uncertain significance. The variant was identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 20 of 281996 chromosomes at a frequency of 0.00007092 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 5 of 30528 chromosomes (freq: 0.000164), Latino in 5 of 35332 chromosomes (freq: 0.000142), Other in 1 of 7194 chromosomes (freq: 0.000139), European (non-Finnish) in 8 of 128648 chromosomes (freq: 0.000062), East Asian in 1 of 19938 chromosomes (freq: 0.00005), but was not observed in the African, Ashkenazi Jewish, or European (Finnish) populations. UMD reports the variant to co-occur with a pathogenic BRCA2 variant, c.6275_6276delTT (p.Leu2092ProfsX7) (from Integrated Genetics ClinVar blurb, SCV000695231.1). The p.Tyr3092 residue is conserved in mammals and more distantly related organisms, and 8 out of 8 computational predictors (MUT Assesor, SIFT, Polyphen2, MT, FATHMM, DANN, MetaLR, Revel) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, the clinical significance of this variant cannot be determined at this time, though we would lean toward a more benign role for this variant. This variant is classified as likely benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735623 SCV000863761 likely benign Breast and/or ovarian cancer 2010-04-21 no assertion criteria provided clinical testing

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