Submissions for variant NM_007294.4(BRCA1):c.5252G>A (p.Arg1751Gln)

gnomAD frequency: 0.00004  dbSNP: rs80357442

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112579	SCV000244393	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 = 0.000206
Invitae	RCV001085532	SCV000076896	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000168520	SCV000209988	likely benign	not specified	2017-08-15	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	RCV000162992	SCV000213480	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	RCV000112579	SCV000488772	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162992	SCV000683277	likely benign	Hereditary cancer-predisposing syndrome	2016-01-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168520	SCV000699228	benign	not specified	2020-11-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5252G>A (p.Arg1751Gln) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 5 splice prediction tools predict that this variant does not affect normal splicing, which was confirmed by an allelic-imbalance assay (Caux-Moncoutier_2009). The variant allele was found at a frequency of 3.6e-05 in 251492 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.1e-05 vs 1.00e-03), allowing no conclusion about variant significance. c.5252G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for causality (Stoppa-Lyonnet_1997, Gad_2002, deJuan_2009). In one large association study, the variant was found to be not associated with risk of breast cancer in the Caucasian population (Shimelis_2017). Multifactorial probability models report a neutral outcome (Easton_2007, Lindor_2012). At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.8346G>A, p.Trp2788X*), providing supporting evidence for a benign role. In addition, multiple functional assays suggest the variant of interest to have normal transcriptional activity, growth and localization activities as well as homology directed repair (example, Lee_2010, Rowling_2010, Williams_2003, and Thouvenot_2016, Lodovichi_2016, Woods_2016, Findlay_2018). Eight clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759558	SCV000888944	likely benign	not provided	2023-04-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000112579	SCV001140477	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112579	SCV001287200	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-28	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	RCV000148392	SCV002043452	benign	Breast and/or ovarian cancer	2023-05-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162992	SCV002537829	likely benign	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168520	SCV004242800	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112579	SCV000145412	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148392	SCV000190091	uncertain significance	Breast and/or ovarian cancer	2014-06-01	no assertion criteria provided	research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000168520	SCV000587483	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001270285	SCV000591600	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Arg1751Gln variant was identified in 6 of 96558 proband chromosomes (frequency: 0.000062) from individuals with breast cancer (Shimelis_2017_28283652, Gad_2002_ 12360411). The variant was found to not be associated with breast cancer in a large case-control study (Shimelis_2017_28283652). Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.8346G>A, p.Trp2788X), providing supporting evidence for a benign role (Integrated Genetics ClinVar submission, SCV000699228.2). The variant was identified in dbSNP (ID: rs80357442), ClinVar (Benign, 3 stars, reviewed by expert panel. Classified as benign by ENIGMA in 2015, Counsyl in 2016, Mendelics in 2019, Ambry in 2014, Women's College in 2014. Classified as likely benign by Quest Diagnostics in 2018, GeneDx in 2017, Invitae in 2019, Integrated Genetics in 2018, Color in 2016, CHEO in 2017. VUS by Mount Sinai, BIC, CSER), Cosmic (Identified in tissue from carcinoma of the breast), LOVD 3.0 (VUS, unclassified, benign), ARUP Laboratories (1 - Not pathogenic or of no clinical significance) databases. The variant was identified in control databases in 10 of 282888 chromosomes at a frequency of 0.00003535 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 2 of 35440 chromosomes (freq: 0.000056), European (non-Finnish) in 7 of 129194 chromosomes (freq: 0.000054), African in 1 of 24966 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. This variant is located in the Brca1 C-terminal (BRCT) domain; a domain that is involved in double-strand break repair. Multiple functional studies suggest the variant is neutral, though one suggested it may result in susceptibility to proteolysis (Petitalot_2019_30257991, Lee_2010_ 20516115, Rowling_2010_20378548, Williams_2004_ 15172985, Thouvenot_2016_ 27802165, Lodovichi_2016_27484786, Mirkovic_2004_ 15172985). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 likely benign.
Brotman Baty Institute, University of Washington	RCV000112579	SCV001242473	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro