Submissions for variant NM_007294.4(BRCA1):c.5153-13A>G

gnomAD frequency: 0.00001  dbSNP: rs45471406

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112529	SCV000244387	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	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 = 0.0000517
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088955	SCV000252820	benign	Hereditary breast ovarian cancer syndrome	2024-12-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000586580	SCV000512316	likely benign	not provided	2019-03-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 21990134, 22505045, 16267036, 15829246, 30209399)
Color Diagnostics, LLC DBA Color Health	RCV000580334	SCV000683262	likely benign	Hereditary cancer-predisposing syndrome	2017-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586580	SCV000699210	benign	not provided	2016-05-02	criteria provided, single submitter	clinical testing	Variant summary: The c.5153-13A>G variant affects a non-conserved intronic nucleotide. Mutation taster predicts benign outcome for this variant. 5/5 in silico tools via Alamut predict this variant does not affect RNA splicing sites. Functional study showed that this variant does not affect splicing (Houdayer_BRCA1&2_HM_2012). This variant is found in 3/119788 control chromosomes at a frequency of 0.000025, which does not exceed maximal expected frequency of a pathogenic allele (0.0010005). This variant has been reported in BrC/OvC patients without evidence for causality. BIC lists one co-occurrence of variant of interest and a pathogenic BRCA1 variant in trans (c.5266dupC/p.Gln1756Profs, also cited in Judkins_2005), further supporting neutrality of our variant of interest. In addition, multiple clinical laboratory/publications classified this variant as benign. Taken together, this variant was classified as benign.
Counsyl	RCV000112529	SCV000785499	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112529	SCV001287201	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267848	SCV002550952	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580334	SCV002641071	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112529	SCV000145351	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1999-12-30	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112529	SCV001243672	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358351	SCV001554056	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.5153-13A>G variant was identified in the literature however the frequency of this variant in an affected population was not provided (Easton 2007, Houdayer 2012, Judkins 2005, Lindor 2012). The variant was also identified in dbSNP (ID: rs45471406) as "With Likely benign allele", ClinVar (classified as benign by Invitae, ENIGMA and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Color and Counsyl; as uncertain significance by BIC), and in LOVD 3.0 (4x ). The variant was identified in control databases in 4 of 245430 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111414 chromosomes (freq: 0.00003), and South Asian in 1 of 30776 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant was identified with a co-occurring pathogenic BRCA1 variant (c.5266dupC (Alias 5385insC) (p.Gln1756Profs)), increasing the likelihood that the c.5153-13A>G variant does not have clinical significance (Judkins 2005). In addition, several Multifactorial likelihood-ratio models showed the variant has odds in favor of neutrality 6799 and posterior probability of being deleterious 5.17√ó10‚àí5 (Easton 2007, Lindor 2012). 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.