Submissions for variant NM_007294.4(BRCA1):c.2286A>T (p.Arg762Ser)

gnomAD frequency: 0.00004  dbSNP: rs273898682

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111817	SCV001161570	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00166 (East Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae	RCV001084129	SCV000075796	benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132175	SCV000187254	benign	Hereditary cancer-predisposing syndrome	2021-04-29	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.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240751	SCV000265885	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Counsyl	RCV000111817	SCV000489265	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000047783	SCV000566093	likely benign	not provided	2019-06-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 14973102, 30111351, 18627636, 25041116, 26852015, 18431501, 28222693, 23175448, 22116506, 28408614, 28961279, 27257965, 26530882, 29470806, 28664506, 30287823, 30702160, 30093976, 31477031)
Color Diagnostics, LLC DBA Color Health	RCV000132175	SCV000903159	likely benign	Hereditary cancer-predisposing syndrome	2016-10-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000047783	SCV001133522	benign	not provided	2018-08-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000111817	SCV001140578	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000111817	SCV001283972	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-03-19	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797614	SCV002041733	benign	not specified	2021-11-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2286A>T (p.Arg762Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 328564 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2286A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or other cancers. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Ten clinical diagnostic laboratories and an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=5, VUS n=5, expert panel benign). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV001797614	SCV002064569	uncertain significance	not specified	2019-06-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504945	SCV002809597	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-03-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000111817	SCV004018683	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-23	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111817	SCV000144367	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-09-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353456	SCV000591376	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Arg762Ser variant was identified in 3 of 1862 proband chromosomes (frequency 0.002) from individuals with breast or ovarian cancer (Cao 2013, Suter 2004, Thirthagiri 2008,Toh 2008) and was identified in 1 of 638 control chromosomes (frequency 0.002) from these studies. All probands from these studies were of Chinese or Malaysian descent. The variant was also identified the BIC database 3X as a variant with unknown clinical importance, and in the ClinVar database (classified with “unknown significance” by Ambry Genetics and BIC). The variant was listed in dbSNP (rs273898682) with a frequency of 0.002 (1000 Genomes project; one allele positive for variant), and in the Exome Aggregation Consortium (ExAC) database in 13 of 8654 chromosomes (frequency: 0.0001502) from a population of East Asian individuals and in 1 of 16508 chromosomes from South Asian individuals. The low frequency observed in these cohorts is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Arg762 residue is conserved in mammals; however, the variant amino acid Serine (Ser) is present in both African clawed frog and purple sea urchin, increasing the likelihood that this variant may not have clinical significance. Computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein and Toh (2008) notes that this residue occurs outside of any known functional domain; 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. This variant is classified as a variant of unknown significance.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250532	SCV002520886	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only