ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4992C>T (p.Leu1664=) (rs142459158)

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Total submissions: 12
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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 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: 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.
Invitae RCV000197558 SCV000253508 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000411124 SCV000488454 likely benign Breast-ovarian cancer, familial 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 Health, Inc 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
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 1 no assertion provided in vitro
King Laboratory,University of Washington RCV001171417 SCV001251322 pathogenic Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research

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