Submissions for variant NM_007294.4(BRCA1):c.547+14del

dbSNP: rs273902771

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080882	SCV000261141	benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579808	SCV000683321	likely benign	Hereditary cancer-predisposing syndrome	2015-05-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000515646	SCV000699259	benign	not specified	2022-02-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.547+14delG involves the deletion of a non-conserved nucleotide located close to a canonical splice site which could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing, and a functional study using a mini-gene system confirmed these predictions, showing no aberrant splicing (Steffensen_2014). The variant allele was found at a frequency of 0.00021 in 274964 control chromosomes (gnomAD v2.1 exomes dataset, and publication data), predominantly within the East Asian subpopulation at a frequency of 0.00087 in the gnomAD database. However, the variant was reported in some East Asian subpopulations with a much higher allele frequency, e.g. in the Korean population, the variant allele was found at a frequency of 0.0024. This frequency is 2.4 fold higher than the estimated maximum expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (0.001), suggesting the variant is a benign polymorphism found primarily in East Asian subpopulations. c.547+14delG has been reported in the literature in individuals (most of them were from the Korean subpopulation), who were affected with breast- and/or ovarian cancer (e.g. Choi_2015, Ryu_2017, Ha_2020, Han_2020), however the variant was also reported in several healthy controls (e.g. Yoon_2016, Dong_2021). Co-occurrences with other pathogenic variants have been reported (e.g. c.5266dup (p.Gln1756ProfsX74), in the UMD database), providing supporting evidence for a benign role. In addition, in a study involving Korean individuals with a suspicion of high risk of familial breast-/ovarian cancer, multifactorial probability was estimated by performing systematic assessments of variants of unknown significance in the BRCA genes (which included analysis of co-occurrence with known deleterious mutations, personal and family history of cancer and tumor pathology), and predicted this variant to be benign (Park_2021). Six ClinVar submitters have assessed the variant since 2014: two classified the variant as benign, three as likely benign, and one as of uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000112728	SCV000785397	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770749	SCV000902233	uncertain significance	Breast and/or ovarian cancer	2023-05-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587246	SCV001249215	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BS1
GeneDx	RCV000587246	SCV001758700	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28111427, 28364669)
Sema4, Sema4	RCV000579808	SCV002537861	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000515646	SCV002551053	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112728	SCV000145611	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-12-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354483	SCV001549111	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.547+14delG variant was identified in 3 of 796 proband chromosomes (frequency: 0.004) from Korean individuals or families with breast or ovarian cancer and was identified in 1 of 842 control chromosomes (frequency: 0.001) from healthy individuals (Choi 2015, Yoon 2016). A functional study using a minigene splicing assay found the variant had no effect on splicing and therefore was determined to be neutral (Steffensen_2014). The variant was also identified in dbSNP (ID: rs273902771) “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: benign by Invitae, likely benign by Color Genomics Inc. and Laboratory Corporation of America, and uncertain significance by CHEO Genetics Diagnostic Laboratory and BIC), Clinvitae (3x), COGR (4 clinical laboratories with conflicting interpretations of pathogenicity), LOVD 3.0 (1x), and was not identified in Cosmic, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587246	SCV001905730	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000515646	SCV001970877	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112728	SCV004244163	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing