Submissions for variant NM_007294.4(BRCA1):c.1487G>A (p.Arg496His)

gnomAD frequency: 0.00060  dbSNP: rs28897677

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111630	SCV000244304	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 = 0.00000188
Invitae	RCV000047494	SCV000075507	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000120286	SCV000167242	benign	not specified	2013-12-12	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	RCV000162601	SCV000213022	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: 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.
Counsyl	RCV000111630	SCV000220299	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-05-08	criteria provided, single submitter	literature only
Pathway Genomics	RCV000111630	SCV000223749	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047494	SCV000494349	benign	Hereditary breast ovarian cancer syndrome	2014-09-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120286	SCV000538438	likely benign	not specified	2016-03-29	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: ExAC: 0.1% (51/66708) European; ClinVar: 5 B/LB, 3 VUS
Genetic Services Laboratory, University of Chicago	RCV000120286	SCV000593685	likely benign	not specified	2017-03-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034727	SCV000602714	benign	not provided	2023-11-30	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162601	SCV000679700	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162601	SCV000682965	likely benign	Hereditary cancer-predisposing syndrome	2015-02-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000034727	SCV000806898	likely benign	not provided	2017-07-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000111630	SCV001140601	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034727	SCV001151335	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	BRCA1: BP4
Illumina Laboratory Services, Illumina	RCV000111630	SCV001287423	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-07-10	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170825	SCV001333443	likely benign	Breast and/or ovarian cancer	2023-06-22	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000047494	SCV002026001	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162601	SCV002538034	likely benign	Hereditary cancer-predisposing syndrome	2021-05-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120286	SCV002551035	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000111630	SCV002556514	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-28	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000111630	SCV000043181	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-03	no assertion criteria provided	research	BS1 based on allele frequency in NFE of 0.000884 in gnomAD. REVEL 0.550.
ITMI	RCV000120286	SCV000084438	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111630	SCV000144110	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000111630	SCV000301431	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353760	SCV000591336	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Arg496His variant was identified in at least 10 of 116730 proband chromosomes (frequency: 0.00009) from individuals or families with breast cancer, and was present in 2 of 1602 control chromosomes (frequency: 0.002) from healthy individuals (Arnold 2002, Bodian 2014, Capanu 2011, Horvath 2013, Schoumacher 2001, Soegaard 2008, Spitzer 2000). The variant was also identified in HGMD, LOVD, the ClinVar database (classified through clinical testing as a benign variant by Invitae and GeneDX), the BIC database (86X with unknown clinical importance), and UMD (15X as a neutral variant). In UMD the variant was identified with a 6 different co-occurring pathogenic BRCA1 variants, and Judkins (2005) also found the variant in trans with a known deleterious variant in BRCA1, increasing the likelihood that the p.Arg496Hisvariant does not have clinical significance. In The variant was identified by the Exome Variant Server project in 8 of 8600 European American alleles (frequency: 0.0009), and in dbSNP (ID: rs28897677) with an allele frequency of 0.002 in the ClinSeq project, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Arg496 residue is not conserved in mammals and the variant amino acid histidine (His) is present in dog and opossum, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein, and in silico studies assessing evolutionary conservation, amino acid properties, or multifactorial probability based models all suggest that the variant is not pathogenic or neutral/of little clinical significance (Abkevich 2004, Capanu 2011, Lee 2008, Lindor 2011, Tavtigian 2006). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000111630	SCV000733657	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120286	SCV001905721	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000120286	SCV001926393	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120286	SCV001955904	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000120286	SCV001970056	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120286	SCV002036615	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000111630	SCV004244127	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing