Submissions for variant NM_007294.4(BRCA1):c.5278-14C>G

gnomAD frequency: 0.00006  dbSNP: rs80358105

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077162	SCV001161517	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 7.93E-10
Counsyl	RCV000077162	SCV000154025	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-03-12	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077162	SCV000195939	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206737	SCV000260046	benign	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000421300	SCV000512318	benign	not specified	2015-06-19	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.
Baylor Genetics	RCV000470071	SCV000540990	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580942	SCV000683280	likely benign	Hereditary cancer-predisposing syndrome	2015-07-20	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077162	SCV000744587	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000421300	SCV000918752	benign	not specified	2022-01-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5278-14C>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. These predictions have been confirmed by functional studies demonstrating the variant has no splicing effect (Spearman_2008, Whiley_2011, Wappenschmidt_2012, Steffensen_2014). The variant allele was found at a frequency of 3.2e-05 in 250986 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5278-14C>G has been reported in the literature in individuals affected with cancer including breast cancer and pancreatic cancer (van der Hout_2006, Spearman_2008, Axilbund_2009, Lu_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with pathogenic variants have been reported (BRCA2 c.5722_5723delCT, p.Leu1908ArgfsX2 [BIC]; BRCA2 unspecified [van der Hout_2006]), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function through utilization of a cell-survival assay in a population of edited haploid HAP1 cells as a measure of functional HDR pathway, reported the variant to be functional (Findlay_2018). Six ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000421300	SCV002550946	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077162	SCV000108959	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-01-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077162	SCV000145433	uncertain significance	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	RCV001353929	SCV000591607	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.5278-14C>G variant was identified in 5 of 8294 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian and pancreatic cancer (Axilbund 2009, Spearman 2008, van der Hout 2006). The variant was also identified in dbSNP (ID: rs80358105), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a likely benign variant by the Sharing Clinical Reports Project (derived from Myriad reports) and Counsyl; classified as unknown clinical importance by BIC), the BIC database (4X with unknown clinical importance), and UMD (3X as an uncertain significance variant). This variant was identified in the Exome Variant Server project in 3 of 13006 European American/African American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 4 of 76380 chromosomes (4 individuals) from a population of European (Non-Finnish) and African individuals, although this low number of observations is not substantive enough to determine its relationship to disease. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Four studies have predicted the variant has no effect on splicing (Spearman 2008, Steffensen 2014, van der Hout 2006, Whiley 2011) and two of them classified it as neutral (Steffensen 2014, van der Hout 2006). 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 predicted benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077162	SCV000733589	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077162	SCV001242541	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001689620	SCV001906130	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000421300	SCV001958300	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077162	SCV004243927	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing