Submissions for variant NM_007294.4(BRCA1):c.4485-10A>G

gnomAD frequency: 0.00001  dbSNP: rs863224420

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197772	SCV000253505	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579627	SCV000683189	likely benign	Hereditary cancer-predisposing syndrome	2016-07-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000758831	SCV000720717	likely benign	not provided	2021-05-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000599872	SCV000887698	benign	not specified	2021-03-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000989881	SCV001140519	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research	RCV001090204	SCV001245502	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000599872	SCV001478708	benign	not specified	2022-04-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4485-10A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. This is supported by functional studies that report no impact of this variant on mRNA splicing and no abnormal transcripts detected by in vitro RNA analysis (Montalban_2019). The variant allele was found at a frequency of 1.2e-05 in 250790 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4485-10A>G has been reported in the literature in one study reporting the mutational spectrum of BRCA1 and BRCA2 genes among hereditary breast cancer families in Chile (Alvarez_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 (n=1)/likely benign (n=5). Based on the evidence outlined above reflecting the emerging consensus, the variant was classified as benign.
Sema4, Sema4	RCV000579627	SCV002537754	likely benign	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000989881	SCV004822657	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing
Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	RCV000197772	SCV000916352	benign	Hereditary breast ovarian cancer syndrome	2019-03-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004554747	SCV004735188	likely benign	BRCA1-related disorder	2023-05-17	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).