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

gnomAD frequency: 0.00001  dbSNP: rs199540030

Total submissions: 14

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 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)