ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1397G>A (p.Arg466Gln) (rs199540030)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132262 SCV000187345 likely benign Hereditary cancer-predisposing syndrome 2019-05-09 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV001509546 SCV000209923 likely benign not provided 2018-07-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28301460, 26941049)
Counsyl RCV000077069 SCV000487783 uncertain significance Breast-ovarian cancer, familial 1 2015-11-17 criteria provided, single submitter clinical testing
Invitae RCV000469966 SCV000549294 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-06 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000159868 SCV000588033 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000159868 SCV000698859 uncertain significance not specified 2019-08-27 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1397G>A (p.Arg466Gln) results in a conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) in the encoded protein sequence. Five 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 251102 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1397G>A has been reported in the literature in a family affected with Hereditary Breast and Ovarian Cancer, but without strong evidence for causality (Zuntini_2018). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014): Multiple laboratories reported the variant with conflicting assessments (3X uncertain significance, 4X benign/likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000132262 SCV000911275 benign Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001509546 SCV001716312 uncertain significance not provided 2020-12-07 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077069 SCV000108866 benign Breast-ovarian cancer, familial 1 2012-03-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354036 SCV000591328 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Arg466Gln variant was identified in dbSNP (ID: rs199540030) “With uncertain significance allele”, UMD (1X as an unclassified variant), GeneInsight COGR database (classified with unknown significance by a clinical laboratory), and in the ClinVar database with conflicting classifications by three submitters (classified as benign by Sharing Clinical Reports Project, derived from Myriad reports; classified as likely benign by GeneDx; classified with uncertain significance by Ambry Genetics). The variant was identified in the 1000 Genomes project (1/5000 chromosomes, frequency 0.0002) and in the Exome Aggregation Consortium (ExAC) database (3/11576 Latino chromosomes, frequency: 0.00026; 3/66722 European (Non-Finnish) chromosomes, frequency: 0.00004); the presence of the variant at these low frequencies is not substantive enough to comment on the relationship of this variant to disease. The variant was not identified in the literature, nor was it identified in any other database searches including HGMD, LOVD, COSMIC, and BIC. The p.Arg466Gln residue is not conserved in mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence. One of five in silico splicing prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the potential creation of a cryptic 3’ splice site downstream of the variant but this information is not very predictive of 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.

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