Submissions for variant NM_000059.3(BRCA2):c.4090A>C (p.Ile1364Leu) (rs56248502)

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113272	SCV000245030	benign	Breast-ovarian cancer, familial 2	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.02236 (African), derived from 1000 genomes (2012-04-30).
Invitae	RCV000044344	SCV000072357	benign	Hereditary breast and ovarian cancer syndrome	2020-12-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131014	SCV000185940	benign	Hereditary cancer-predisposing syndrome	2014-07-29	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	RCV000113272	SCV000195981	benign	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000113272	SCV000220319	benign	Breast-ovarian cancer, familial 2	2014-05-14	criteria provided, single submitter	literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000120319	SCV000225186	benign	not specified	2014-07-16	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000113272	SCV000383693	likely benign	Breast-ovarian cancer, familial 2	2018-11-01	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.
Illumina Clinical Services Laboratory,Illumina	RCV000389513	SCV000383694	likely benign	Fanconi anemia, complementation group D1	2018-11-01	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044344	SCV000494323	benign	Hereditary breast and ovarian cancer syndrome	2014-04-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000469910	SCV000541050	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120319	SCV000593715	benign	not specified	2017-11-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001282919	SCV000602753	benign	none provided	2019-12-12	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131014	SCV000679717	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000131014	SCV000683601	benign	Hereditary cancer-predisposing syndrome	2015-03-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113272	SCV000743295	benign	Breast-ovarian cancer, familial 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113272	SCV000744451	benign	Breast-ovarian cancer, familial 2	2017-05-31	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000120319	SCV000805704	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000770724	SCV000902203	benign	Breast and/or ovarian cancer	2016-03-08	criteria provided, single submitter	clinical testing
ITMI	RCV000120319	SCV000084471	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113272	SCV000146371	uncertain significance	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000113272	SCV000591890	benign	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing	The p.Ile1364Leu variant has been previously observed in our laboratory, and has been reported in the literature in 11/2200 proband chromosomes of individuals with breast cancer. However, no controls were tested to establish the frequency of the variant in the general population (Borg_2010_, Caux-Moncoutier_2009_, Haffty_2006_, Haffty_2009_, Tazzite_2012_). It is listed in the dbSNP database as coming from a "clinical source" (ID#:rs56248502) with a global minor allele frequency (MAF) of 0.005 (1000 Genomes). The variant has been reported in the UMD (x17), BIC (x53) and CNPHI databases. In the UMD database, the variant was observed to co-occur with other BRCA2 pathogenic mutations: c.6159delT (p.Ala2054LeufsX16) and c.8548_8551delGAAG (p.Glu2850GlnfsX12), increasing the likelihood that the p.Ile1364Leu variant does not have any clinical significance. This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the p.Ile1364Leu variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113272	SCV000733253	benign	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656601	SCV000778671	likely benign	not provided	2017-08-09	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131014	SCV000787929	likely benign	Hereditary cancer-predisposing syndrome	2018-01-03	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000120319	SCV001906090	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000120319	SCV001958655	benign	not specified		no assertion criteria provided	clinical testing