Submissions for variant NM_007294.4(BRCA1):c.2458A>G (p.Lys820Glu)

gnomAD frequency: 0.00964  dbSNP: rs56082113

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111865	SCV000244319	benign	Breast-ovarian cancer, familial, susceptibility to, 1	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 = 0.00000000000204. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.06098 (African), derived from 1000 genomes (2012-04-30).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047846	SCV000075859	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000111865	SCV000154020	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-02-14	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories, University of Michigan	RCV000111865	SCV000195905	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162590	SCV000213007	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
Eurofins Ntd Llc (ga)	RCV000120273	SCV000225004	benign	not specified	2014-07-01	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000162590	SCV000267009	likely benign	Hereditary cancer-predisposing syndrome	2016-01-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162590	SCV000292127	benign	Hereditary cancer-predisposing syndrome	2014-12-06	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000120273	SCV000297224	benign	not specified	2015-07-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120273	SCV000311790	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000111865	SCV000403065	benign	Breast-ovarian cancer, familial, susceptibility to, 1	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	RCV000047846	SCV000494356	benign	Hereditary breast ovarian cancer syndrome	2014-02-12	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000047846	SCV000576443	likely benign	Hereditary breast ovarian cancer syndrome	2017-02-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034732	SCV000602692	benign	not provided	2023-11-16	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000120273	SCV000693607	benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000111865	SCV000744656	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162590	SCV000803151	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000047846	SCV002025980	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000047846	SCV002515191	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162590	SCV002538127	benign	Hereditary cancer-predisposing syndrome	2020-04-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120273	SCV002551019	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477057	SCV002803657	benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-08-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000111865	SCV004016775	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034732	SCV004140629	benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000034732	SCV005251068	benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034732	SCV000043176	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120273	SCV000084425	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111865	SCV000144442	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000111865	SCV000187729	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-07-24	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120273	SCV000591389	benign	not specified		no assertion criteria provided	clinical testing	The p.Lys820Glu variant has been identified in 7 of 4428 proband chromosomes (frequency 0.002) in individuals with breast or ovarian cancers (Capanu 2011, Fackenthal 2005, Jalkh 2012); however control chromosomes from healthy individuals were not included in these studies. This variant was identified in dbSNP (rs56082113) and with a frequency of 3% in the African American population from the Exome Variant Server. The variant was also reported 30x in BIC as a variant of unknown clinical importance, and 10x in the UMD as a neutral variant which co-occurred with a known BRCA1 pathogenic mutation (c.3607C>T (p.Arg1203X)). The p.Lys820 residue is not conserved in evolution and the variant amino acid (Glu) is present in macaque and opossum. Furthermore, computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, and two in silico studies have concluded this variant to be neutral or of little clinical significance (Lindor 2012, Tavtigian 2006); however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000034732	SCV000778756	likely benign	not provided	2018-02-19	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735498	SCV000863636	benign	Breast and/or ovarian cancer	2013-04-23	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120273	SCV001905835	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120273	SCV001954883	benign	not specified		no assertion criteria provided	clinical testing