ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.19C>T (p.Arg7Cys) (rs80356994)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085456 SCV000075689 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-28 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 Intact protein function observed in appropriate functional assay(s);Other strong data supporting benign classification
GeneDx RCV000428757 SCV000515777 likely benign not specified 2017-04-12 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.
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 Health, Inc 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 2018-07-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000428757 SCV001360566 likely benign not specified 2020-09-28 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. The variant has been reported to impart only a mild reduction in HDR acitvity compared to wild-type, 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). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=6) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031021 SCV000053614 likely benign Breast-ovarian cancer, familial 1 2011-07-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031021 SCV000144046 uncertain significance Breast-ovarian cancer, familial 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 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.

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