Submissions for variant NM_007294.4(BRCA1):c.2521C>T (p.Arg841Trp)

gnomAD frequency: 0.00137  dbSNP: rs1800709

Total submissions: 42

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019251	SCV000244321	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 = 0.00000000000229
Invitae	RCV000047867	SCV000075880	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000019251	SCV000154021	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-02-18	criteria provided, single submitter	literature only
GeneDx	RCV000120283	SCV000167280	benign	not specified	2013-11-04	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	RCV000162566	SCV000212979	benign	Hereditary cancer-predisposing syndrome	2014-07-14	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000019251	SCV000267702	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000047867	SCV000297225	likely benign	Hereditary breast ovarian cancer syndrome	2015-11-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120283	SCV000311791	benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120283	SCV000336440	benign	not specified	2015-10-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047867	SCV000494310	benign	Hereditary breast ovarian cancer syndrome	2014-10-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120283	SCV000538437	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: 0.2% (145/66714) European chromosomes; ClinVar: 7 labs classify as benign
Baylor Genetics	RCV000457953	SCV000540974	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120283	SCV000586885	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034733	SCV000600292	benign	not provided	2023-03-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162566	SCV000683041	likely benign	Hereditary cancer-predisposing syndrome	2014-12-13	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000019251	SCV000743415	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000019251	SCV000744655	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000019251	SCV001140573	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034733	SCV001156725	benign	not provided	2023-08-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000019251	SCV001280881	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-01-30	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170820	SCV001333438	benign	Breast and/or ovarian cancer	2019-03-14	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000457953	SCV001369371	likely benign	Familial cancer of breast	2019-11-08	criteria provided, single submitter	clinical testing	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BP1,BP4,BP6.
Genetics Program, Instituto Nacional de Cancer	RCV000047867	SCV002515192	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162566	SCV002538132	benign	Hereditary cancer-predisposing syndrome	2020-07-15	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034733	SCV002545930	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BS1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120283	SCV002551017	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490393	SCV002802929	benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-03-22	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000019251	SCV004016783	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
OMIM	RCV000019251	SCV000039539	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-11-01	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034733	SCV000043175	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
Sharing Clinical Reports Project (SCRP)	RCV000019251	SCV000053650	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-01	no assertion criteria provided	clinical testing
ITMI	RCV000120283	SCV000084435	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019251	SCV000144466	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	RCV000019251	SCV000301432	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	RCV000120283	SCV000591392	benign	not specified		no assertion criteria provided	clinical testing	The p.Arg841Trp variant has been previously reported in 16/8958 proband chromosomes (frequency: 0.002) in individuals with breast or ovarian cancer, however, no controls were included in these studies (Barker 1996, Borg 2010, Diez 2003, Janezic 1999, Pal 2004, Shattuck-Eidens 1997). The variant was also listed in the dbSNP database as having an average heterozygosity of 0.006+/-0.056 (ID#:rs1800709), increasing the likelihood this variant does not have clinical significance. The p.Arg841 residue is not conserved in mammals or lower organisms; however, computational analyses (SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. There are also numerous studies in the literature which have attempted to classify this variant using different modeling appoaches but the effect of this variant on protein function remains undetermined (Burk Herrick 2006, Chenevix-Trench 2006, Goldgar 2004, Fleming 2003, Lindor 2011, Petersen 1998). Notably, this variant was reported in the UMD database, 54 times and in 6 individuals with a second pathogenic variant in either the BRCA1 or BRCA2 genes, increasing the likelihood the p.Arg841Trp variant is benign. It is also reported 114 times in the BIC database with unknown clinical consequence, although this high frequency might suggest it is a common benign polymorphism. Finally, this variant was reported by Myriad as a common polymorphism. In summary, based on the above information, this variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000019251	SCV000733641	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034733	SCV000778755	benign	not provided	2017-03-08	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162566	SCV000787898	likely benign	Hereditary cancer-predisposing syndrome	2017-10-10	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120283	SCV001800207	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120283	SCV001905820	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120283	SCV001951674	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000019251	SCV004244087	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing