Submissions for variant NM_000059.4(BRCA2):c.7319A>G (p.His2440Arg)

gnomAD frequency: 0.00984  dbSNP: rs4986860

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113748	SCV000245108	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.03049 (African), derived from 1000 genomes (2012-04-30).
Invitae	RCV000167852	SCV000073200	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000113748	SCV000154046	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000120351	SCV000202299	benign	not specified	2014-12-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162498	SCV000212885	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: seen in unaffected individuals, 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.
Pathway Genomics	RCV000113748	SCV000223769	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-30	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000167852	SCV000257618	likely benign	Hereditary breast ovarian cancer syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113748	SCV000267806	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768607	SCV000324840	benign	Breast and/or ovarian cancer	2016-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000305952	SCV000383764	benign	Fanconi anemia complementation group D1	2018-01-13	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000113748	SCV000383765	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-13	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167852	SCV000494342	benign	Hereditary breast ovarian cancer syndrome	2014-02-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000474872	SCV000541039	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120351	SCV000586973	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034458	SCV000602877	benign	not provided	2023-11-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162498	SCV000683865	benign	Hereditary cancer-predisposing syndrome	2015-03-05	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113748	SCV000744514	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120351	SCV000805759	benign	not specified	2017-04-13	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000167852	SCV002025814	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000167852	SCV002515141	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162498	SCV002531850	benign	Hereditary cancer-predisposing syndrome	2020-03-24	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002504865	SCV002809287	benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-04-13	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113748	SCV004016843	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034458	SCV004132993	benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120351	SCV004243061	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113748	SCV004844395	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000113748	SCV000043225	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-06	no assertion criteria provided	research	BA1 based on allele frequency in AFR of 0.03316 in gnomAD.
ITMI	RCV000120351	SCV000084503	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113748	SCV000147070	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353451	SCV000592106	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.His2440Arg variant has been previously reported in the literature in 8/13066 proband chromosomes from individuals with breast and ovarian cancer, as well as in 4/280 control chromosomes (Fackenthal_2005_15744044, Gao_2000_11030417, Akbari_2011_21965345, Borg_2010_20104584, Haffty_2009_19491284). It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs4986860) with a MAF score of 0.007 (1000 Genomes). The variant was identified in the ExAc Database at a frequency of 0.003 which includes 9 homozygous individuals and a 0.03 frequency in the African population. The variant was also identified in the UMD (x24), BIC (x79), Exome Server and BOCs databases. In the UMD database, the p.His2440Arg variant was found to co-occur with pathogenic mutations in BRCA1 c.IVS16+6T>C (c.4986+6T>C), as well as in BRCA2 c.2808_2811delACAA (p.Ala938ProfsX21); c.7069_7070delCT (p.Leu2357ValfsX2), increasing the likelihood that the variant is a benign alteration. This residue is not conserved in mammals and computational analyses (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, this variant is classified as Benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000034458	SCV000778706	likely benign	not provided	2017-10-09	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162498	SCV000787948	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120351	SCV001906233	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120351	SCV001958535	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000120351	SCV001978209	benign	not specified		no assertion criteria provided	clinical testing