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

Total submissions: 31

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