Submissions for variant NM_007294.4(BRCA1):c.3083G>A (p.Arg1028His)

gnomAD frequency: 0.00106  dbSNP: rs80357459

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031088	SCV000244332	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 = 0.00000998
Invitae	RCV000048067	SCV000076080	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000588855	SCV000108664	likely benign	not provided	2020-07-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 28717660, 28364669, 9333265, 26689913, 21990134, 15235020, 16267036, 22366370, 17924331, 10699917, 22753008)
Ambry Genetics	RCV000129147	SCV000183868	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	RCV000031088	SCV000220927	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-12-01	criteria provided, single submitter	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000048067	SCV000297226	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-12-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129147	SCV000537499	likely benign	Hereditary cancer-predisposing syndrome	2015-04-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588855	SCV000699002	benign	not provided	2016-03-24	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a missense change involving a non-conserved nucleotide with 3/4 in silico programs predicting a "benign" outcome (SNPs&GO not captured here due to low reliability index). The variant of interest was observed in a large, broad control population, ExAC with an overall allele frequency of 21/121360 (1/5780), however, the variant is predominantly observed in the Latino population with an allele frequency of 19/11576 (1/609), which exceeds the maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. Therefore, suggesting that the variant of interest is a common polymorphism specifically found in population(s) of Latino origin. In addition, the variant of interest has been found in affected individuals, with limited co-occurrence and co-segregation information but has been observed to co-occur with another BRCA1 variant, c.5165C>T (p.Ser1722Phe), which was previously classified as VUS-possibly pathogenic and with a pathogenic BRCA2 variant c.771_775delTCAAA p.Asn257_Arg259fs indicating neutrality. Furthermore, the variant of interest has been classified by multiple reputable databases and clinical laboratories via ClinVar, along with publications, Easton_2007 and Lindor_2012, all which classify the variant as "neutral/likely neutral." Therefore, taking all available lines of evidence, the variant of interest is classified as Benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129147	SCV000803150	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000588855	SCV000806928	likely benign	not provided	2018-01-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031088	SCV001287307	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-02-15	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588855	SCV001471659	likely benign	not provided	2019-11-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120292	SCV002068141	likely benign	not specified	2020-09-14	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000048067	SCV002504998	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129147	SCV002538181	likely benign	Hereditary cancer-predisposing syndrome	2021-01-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120292	SCV002551007	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496475	SCV002808066	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-11-29	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153310	SCV003843369	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031088	SCV000053684	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2006-10-03	no assertion criteria provided	clinical testing
ITMI	RCV000120292	SCV000084444	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031088	SCV000144630	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120292	SCV000591424	benign	not specified		no assertion criteria provided	clinical testing	The p.Arg1028 variant has been reported in the literature in 9/111500 proband chromosomes of individuals with HBOC and brain cancer, although no control chromosomes were tested to establish the frequency in the general population (Abkevich_2004, Judkins_2005a, Lindor_2012, Spitzer_2000). It has also been identified in the BIC (x13), BOCs (classified as ACMG 3), and LOVD databases. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs80357459) with a MAF score of 0.001 (1000 Genomes). This residue is not conserved in mammals and the variant amino acid Histidine (His) is present in the macaque at this position, increasing the likelihood that an alteration to this residue may not have functional significance. Computational analyses (PolyPhen, SIFT, AlignGVGD) do not predict any effect on the protein function, however, this information is not predictive enough to assume pathogenicity. Myriad reports this variant as being a "polymorphism" increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.