Submissions for variant NM_007294.4(BRCA1):c.4992C>T (p.Leu1664=)

gnomAD frequency: 0.00061  dbSNP: rs142459158

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000411124	SCV000577998	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0012 (African), derived from ExAC (2014-12-17).
GeneDx	RCV000123930	SCV000167317	benign	not specified	2014-02-05	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.
Ambry Genetics	RCV000162626	SCV000213061	likely benign	Hereditary cancer-predisposing syndrome	2014-09-26	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197558	SCV000253508	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000411124	SCV000488454	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000471497	SCV000540987	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162626	SCV000683236	benign	Hereditary cancer-predisposing syndrome	2016-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123930	SCV000916743	benign	not specified	2018-12-10	criteria provided, single submitter	clinical testing	Variant summary: The variant, BRCA1 c.4992C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 0.00016 in 279004 control chromosomes, predominantly at a frequency of 0.0015 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.4992C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins _2005, Fackenthal _2012, Zheng _2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, but without a conclussive result (Findlay _2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508809	SCV001715195	uncertain significance	not provided	2020-10-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001508809	SCV002050144	benign	not provided	2023-10-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000123930	SCV002068395	likely benign	not specified	2018-02-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162626	SCV002537802	benign	Hereditary cancer-predisposing syndrome	2020-11-26	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000197558	SCV004014947	likely benign	Hereditary breast ovarian cancer syndrome	2023-01-24	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353813	SCV000591559	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Leu1664= variant was identified in 17 of 112062 proband chromosomes (frequency: 0.00015) from individuals or families with breast cancer (Fackenthal 2012, Judkins 2005). Judkins (2005) performed a large computational study based on the segregation of variants with certain haplogypes to characterize the clinical significance of genetic variants and concluded that the variant was a benign polymorphism. The variant was also identified in dbSBP (ID: rs142459158) as “With Likely benign allele”, ClinVar (as likely benign by Ambry Genetics, Invitae, and Counsyl, and as benign by GeneDx and Baylor Genetics), Clinvitae (4x), and UMD-LSDB (9x as uncertain significance) databases. The variant was not identified in Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was also identified by our laboratory in 2 individuals with breast cancer. The variant was identified in control databases in 44 of 277010 chromosomes at a frequency of 0.000159 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu1664=variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.
Brotman Baty Institute, University of Washington	RCV000411124	SCV001243348	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
King Laboratory, University of Washington	RCV001171417	SCV001251322	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Hereditary breast ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000123930	SCV001906345	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001508809	SCV001972451	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554710	SCV004774406	likely benign	BRCA1-related disorder	2021-05-18	no assertion criteria provided	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).