ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1151C>T (p.Ser384Phe) (rs41293475)

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Total submissions: 31
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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) RCV000112886 SCV000244418 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 = 0.000424
Invitae RCV000043747 SCV000071760 benign Hereditary breast and ovarian cancer syndrome 2020-11-26 criteria provided, single submitter clinical testing
GeneDx RCV000120306 SCV000108596 benign not specified 2017-07-25 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.
Counsyl RCV000112886 SCV000154036 likely benign Breast-ovarian cancer, familial 2 2014-01-02 criteria provided, single submitter literature only
Ambry Genetics RCV000162684 SCV000213138 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000112886 SCV000267742 likely benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112886 SCV000383628 likely benign Breast-ovarian cancer, familial 2 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000120306 SCV000538482 uncertain significance not specified 2016-03-28 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: Multiple publications classify as VUS/not pathogenic; ExAC: 0.1% (69/66720) European chromosomes
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000120306 SCV000586925 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120306 SCV000593701 likely benign not specified 2015-08-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034428 SCV000602838 benign not provided 2017-09-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162684 SCV000683404 likely benign Hereditary cancer-predisposing syndrome 2015-02-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034428 SCV000692768 likely benign not provided 2020-03-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000112886 SCV000743256 benign Breast-ovarian cancer, familial 2 2014-10-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000112886 SCV000744403 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034428 SCV000805647 likely benign not provided 2018-01-17 criteria provided, single submitter clinical testing
Mendelics RCV000112886 SCV001138990 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001112104 SCV001269725 uncertain significance Fanconi anemia, complementation group D1 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Research and Development, ARUP Laboratories RCV001642536 SCV001854667 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034428 SCV000043196 probably not pathogenic not provided 2012-07-13 no assertion criteria provided research Converted during submission to Likely benign.
ITMI RCV000120306 SCV000084458 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000112886 SCV000145823 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148428 SCV000190127 uncertain significance Breast neoplasm 2014-06-01 no assertion criteria provided research
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000120306 SCV000587580 benign not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120306 SCV000591730 benign not specified no assertion criteria provided clinical testing The p.Ser384Phe variant has been previously observed in our laboratory, and has also been reported in the literature in 127/92430 proband chromosomes of individuals with breast cancer and/ HBOC. It has also been reported in 13/8580 control chromosomes tested (selected publications: Capanu_2011, Chenevix-Trench_2006, Wappenschmidt_2005, Hondow_2011, Johnston_2012, Salazar_2006). In one study, four women from a large kindred suffering from breast cancer were analysed, and the variant was identified in 3/4 women with breast cancer. It was also observed to co-occurr 5 times with the different deleterious mutations Q258X, K2013X, S2219X, 3036del4 and 2046X (German Consortium for Hereditary Breast and Ovarian Cancer and by Myriad Genetic Laboratories). Based on these observations, the authors of the study classified p.Ser384PHe as neutral on the basis of co-occurrence with pathogenic variants and non-cosegregation with disease (Wappenschmidt_2005). The variant has been reported in the UMD (x26), BIC (x143), BOCs and Exome Variant Server databases. In the UMD database, it has been observed to co-occur with the following pathogenic mutations in BRCA1: c.3285delA (p.Lys1095AsnfsX14), c.191G>A (p.Cys64Tyr), c.5128G>T (p.Gly1710X), c.282_288dup (p.Thr97AlafsX2), as well as in BRCA2: c.1796_1800delCTTAT (p.Ser599X), c.2376C>G (p.Tyr792X), increasing the likelihood that the p.Ser384Phe variant does not have any clinical significance. It is listed in the dbSNP database as coming from a "clinical source" (ID#:41293475), but no frequency information was provided, and so the prevalence of this variant in the population is not known. This residue is not conserved in mammals. Computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein; however, this information is not very predictive of pathogenicity. In summary, based on the above information, this variant is classified as Benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000112886 SCV000733224 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000034428 SCV000778641 likely benign not provided 2016-12-08 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735441 SCV000863577 uncertain significance Breast and/or ovarian cancer 2001-08-21 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000120306 SCV001799137 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000120306 SCV001906338 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000120306 SCV001951260 benign not specified no assertion criteria provided clinical testing

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