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

gnomAD frequency: 0.00024  dbSNP: rs80358111

Total submissions: 19

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	2024-01-30	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, part of Exact Sciences	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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000159887	SCV002760924	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149772	SCV003838896	likely benign	Breast and/or ovarian cancer	2021-08-09	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000195733	SCV004014957	benign	Hereditary breast ovarian cancer syndrome	2023-04-11	criteria provided, single submitter	clinical testing
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