Submissions for variant NM_000059.4(BRCA2):c.8567A>C (p.Glu2856Ala) (rs11571747)

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000167825	SCV000073571	benign	Hereditary breast and ovarian cancer syndrome	2020-12-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000031751	SCV000154095	likely benign	Breast-ovarian cancer, familial 2	2014-04-08	criteria provided, single submitter	literature only
GeneDx	RCV000152885	SCV000167412	benign	not specified	2014-01-07	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.
Ambry Genetics	RCV000131022	SCV000185950	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	RCV000031751	SCV000196016	benign	Breast-ovarian cancer, familial 2	2014-11-03	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000152885	SCV000202304	likely benign	not specified	2014-05-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000735613	SCV000219411	likely benign	Breast and/or ovarian cancer	2019-04-18	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167825	SCV000267847	likely benign	Hereditary breast and ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000371112	SCV000383788	likely benign	Fanconi anemia, complementation group D1	2018-02-28	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	RCV000031751	SCV000383789	likely benign	Breast-ovarian cancer, familial 2	2018-02-28	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	RCV000167825	SCV000494364	benign	Hereditary breast and ovarian cancer syndrome	2014-09-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000152885	SCV000538491	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: ClinVar: 10 labs classify as LB/Ben; ExAC: 0.1% (94/66682) European chromosomes
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency	RCV000152885	SCV000586982	benign	not specified	2017-04-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001282957	SCV000602794	benign	none provided	2020-06-26	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000131022	SCV000683983	likely benign	Hereditary cancer-predisposing syndrome	2014-11-25	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031751	SCV000743349	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	RCV000031751	SCV000744542	benign	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131022	SCV000747808	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000034464	SCV000805782	likely benign	not provided	2017-08-25	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000034464	SCV001148998	likely benign	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Research and Development, ARUP Laboratories	RCV001642482	SCV001852801	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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034464	SCV000043231	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
Sharing Clinical Reports Project (SCRP)	RCV000031751	SCV000054359	benign	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031751	SCV000147403	benign	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000031751	SCV000207353	likely benign	Breast-ovarian cancer, familial 2	2014-11-06	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000152885	SCV000592209	benign	not specified		no assertion criteria provided	clinical testing	The p.Glu2856Ala variant is identified in the literature in 26 out of 7714 proband chromosomes (frequency 0.003) with breast, ovarian and prostate cancers, however it is also identified in 16 out of 5286 control chromosomes (frequency 0.003) (Spitzer 2000, Borg 2010, Soegaard 2008, Edwards 2003, Chenevix-Trench 2006, Evans 2008), and listed in dbSNP database as coming from a "clinical source" (ID#: rs11571747) with an average heterozygosity of 0.002+/-0.031 in various human populations, therefore increasing the likelihood of this variant to be benign. In the UMD database, this variant has been identified in two (out of 23) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 or BRCA2 mutation was also detected, and also found in an breast cancer individual in the homozygous state (Chenevix-Trench 2006), further suggesting the benign nature of this variant. The p.Glu2856 residue is conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, leaning more towards deleterious, but this information is not predictive enough to assume pathogenicity. Furthermore, Myriad genetics has reported this variant as a polymorphism increasing the likelihood this variant is benign (personal communication). Based on the above information, this variant is classified as Benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031751	SCV000733319	benign	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131022	SCV000787955	likely benign	Hereditary cancer-predisposing syndrome	2017-08-14	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735613	SCV000863751	uncertain significance	Breast and/or ovarian cancer	2001-08-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034464	SCV001800804	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000152885	SCV001906421	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000152885	SCV001951665	benign	not specified		no assertion criteria provided	clinical testing