ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4358-10C>T

gnomAD frequency: 0.00024  dbSNP: rs80358111
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159887 SCV000209971 benign not specified 2014-08-04 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.
Counsyl RCV000112326 SCV000220849 likely benign Breast-ovarian cancer, familial, susceptibility to, 1 2014-10-31 criteria provided, single submitter literature only
Invitae RCV000195733 SCV000252817 benign Hereditary breast ovarian cancer syndrome 2021-12-18 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000579629 SCV000683175 benign Hereditary cancer-predisposing syndrome 2015-10-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587967 SCV000699139 benign not provided 2016-03-28 criteria provided, single submitter clinical testing Variant Summary: The c.4358-10C>T variant involves the alteration of a non-conserved nucleotide resulting in an intronic change. 5/5 in silico tools via Alamut predict no significant effect on splicing and an in vitro assay showed evidence that the variant does not affect splicing (Houdayer_2012). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.023%, predominantly in individuals of Europeand and Latino origin (0.035%). The variant has been reported to co-occur with a different deleterious BRCA1/2 variants suggesting a non-pathogenic nature of this variant. Additionally, the variant has been reported in the homozygous state further supporting neutrality. Lastly, several reputable databases and clinical diagnostic labs have classifed the variant as "Benign". Taken together, this variant has been classified as Benign.
PreventionGenetics,PreventionGenetics RCV000587967 SCV000806950 likely benign not provided 2018-01-02 criteria provided, single submitter clinical testing
Mendelics RCV000112326 SCV001140524 likely benign Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000587967 SCV001159131 benign not provided 2022-01-25 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000112326 SCV001280760 likely benign Breast-ovarian cancer, familial, susceptibility to, 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory,University of Chicago RCV000159887 SCV002068648 likely benign not specified 2021-02-26 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000579629 SCV002537743 likely benign Hereditary cancer-predisposing syndrome 2021-01-31 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000112326 SCV000145073 benign Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000159887 SCV000591511 benign not specified no assertion criteria provided clinical testing The BRCA1 c.4358-10C>T variant was identified in 7 of 5548 proband chromosomes from individuals with breast or ovarian cancer and was not identified in 200 control chromosomes from these studies (Borg 2010, Diez 2003, Konstantopoulou 2008). This variant was also identified in the following databases: dbSNP (ID: rs80358111) “With untested allele”, LOVD, UMD (14X as a neutral variant), and BIC (25X with no clinical importance). In UMD, this variant was twice reported to co-occur with known pathogenic mutations (BRCA1 c.4195_4196delAC (p.Thr1399HisfsX4) and BRCA2 c.IVS12+594T>G (c.6937+594T>G)), increasing the likelihood that it does not have clinical significance. Furthermore, Judkins (2005) identified the c.4358-10C>T variant residing in trans with a known deleterious mutation in BRCA1, and Konstantopoulou (2008) identified the variant in a homozygous state in one individual, suggesting that this variant is not associated with disease as there is strong evidence that biallelic BRCA1 deleterious mutations result in embryonic lethality. The variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions; however, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict any change in splicing for this variant but this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Hereditary Cancer Genetics group,Vall d'Hebron Institute of Oncology RCV000195733 SCV000916350 benign Hereditary breast ovarian cancer syndrome 2019-03-01 no assertion criteria provided research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000159887 SCV001951050 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000159887 SCV001971162 benign not specified no assertion criteria provided clinical testing

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