ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs199540030
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Total submissions: 14
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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 This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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 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, susceptibility to, 1 2015-11-17 criteria provided, single submitter clinical testing
Invitae RCV000469966 SCV000549294 likely benign Hereditary breast ovarian cancer syndrome 2024-01-16 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 likely benign not specified 2022-09-18 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) of 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 as a VUS in settings of a family with breast cancer and in individuals undergoing germline BRCA1/2 cancer testing (example, Zuntini_2018. Kim_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001509546 SCV002046110 likely benign not provided 2023-02-06 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000132262 SCV002538021 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-17 criteria provided, single submitter curation
University of Washington Department of Laboratory Medicine, University of Washington RCV000132262 SCV003851322 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP) RCV000077069 SCV000108866 benign Breast-ovarian cancer, familial, susceptibility to, 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.
Department of Medical and Surgical Sciences, University of Bologna RCV000077069 SCV004228330 benign Breast-ovarian cancer, familial, susceptibility to, 1 2023-09-01 no assertion criteria provided clinical testing BS1(Supporting)+BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - (PMID: 38160042)

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