Submissions for variant NM_007294.4(BRCA1):c.19C>T (p.Arg7Cys)

gnomAD frequency: 0.00002  dbSNP: rs80356994

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001085456	SCV000075689	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130702	SCV000185589	likely benign	Hereditary cancer-predisposing syndrome	2018-01-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000758790	SCV000515777	likely benign	not provided	2020-08-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20859677, 23961350, 26109977, 11573085, 23192404, 21918854, 32123317, 22684231, 16403807, 24312913, 25823446, 30209399, 31131967)
Department of Pathology and Molecular Medicine, Queen's University	RCV000428757	SCV000588021	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130702	SCV000683006	likely benign	Hereditary cancer-predisposing syndrome	2017-01-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758790	SCV000887632	likely benign	not provided	2023-07-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000428757	SCV001360566	likely benign	not specified	2023-07-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.19C>T (p.Arg7Cys) 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 2.4e-05 in 251176 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.19C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples- Gonzalez_2011, Keshvarzi_2012, Solano_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant, suggesting a benign functional effect (examples Starita_2015, Bouwman_2020), and has been reported to not have an effect on splicing (Wai_2020). The variant has also been reported to have normal binding to BARD1 and E2, and have normal levels of E3 ligase activity (Morris_2006). The following publications have been ascertained in the context of this evaluation (PMID: 32546644, 20683152, 35659930, 30209399, 20859677, 34981296, 16267036, 21918854, 16403807, 23192404, 23961350, 25823446, 32123317). Seven other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant with a majority consensus as as likely benign (n=6) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492308	SCV004240250	likely benign	Breast and/or ovarian cancer	2023-01-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944847	SCV004759969	likely benign	BRCA1-related condition	2019-02-27	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000031021	SCV000053614	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-07-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031021	SCV000144046	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000130702	SCV000805229	likely benign	Hereditary cancer-predisposing syndrome	2018-03-15	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031021	SCV001237684	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354707	SCV001549389	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Arg7Cys variant was identified in 5 of 516 proband chromosomes (frequency: 0.0097) from Argentinean, Iranian and Algerian individuals or families with HBOC (Cherbal 2012, Solano 2012, Keshavarzi 2012). The variant was also identified in dbSNP (ID: rs80356994) as "With other allele", ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Color, Invitae, Quest Diagnostics, SCRP, and True Health Diagnostics; as uncertain significance by Queen's University and BIC), LOVD 3.0 (3 submissions, classified as does not affect function and effect unknown), UMD-LSDB (classified as a probable polymorphism).The variant was identified in control databases in 6 of 245822 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 6 of 111308 chromosomes (freq: 0.000054), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In a yeast two-hybrid ubiquitin ligase assay this variant showed E2 and BARD1 binding and E3 ligase activity equivalent to wild type function (Morris 2006). In a massively parallel functional analysis of BRCA1 RING domain variants, this variant showed no binding defect with BARD1 and was able to rescue homology-directed DNA repair but it performed poorly in the E3 ligase selections; however, it may retain enough E3 ligase activity to satisfy a possibly low threshold of requisite activity and was classified as benign (Starita 2015). The p.Arg7 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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.