Submissions for variant NM_007294.4(BRCA1):c.548-17G>T

gnomAD frequency: 0.00028  dbSNP: rs80358014

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031256	SCV000244403	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 = 0.000000319
GeneDx	RCV000123884	SCV000167229	benign	not specified	2014-02-24	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080593	SCV000252821	benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000031256	SCV000488470	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586208	SCV000602721	benign	not provided	2023-03-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580272	SCV000683325	benign	Hereditary cancer-predisposing syndrome	2015-02-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586208	SCV000699264	benign	not provided	2016-06-07	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.548-17G>T variant causing the alteration of a non-conserved intronic nucleotide with 5/5 in silico programs predicting no significant effect on splicing, which is supported by multiple functional studies. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 20/119928 (1/5995, frequency: 0.0001668), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000 (0.0010005). The variant of interest has been reported in multiple affected individuals via publications with limited information (ie, lack of co-occurrence and cosegregation data). However, the variant has been reported to co-occur with other pathogenic variants, BRCA1, c.2722G>T and BRCA2 variants, c.8237_8238delCA (p.Thr2736SerfsX17), c.2930_2940del and c.1202C>A (p.Ser401X). In addition, multiple publications and reputable databases/clinical laboratories cite the variant as "Benign/Neutral." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000123884	SCV000806976	benign	not specified	2017-06-29	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196702	SCV001367333	benign	Familial cancer of breast	2019-10-17	criteria provided, single submitter	clinical testing	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BP6,BP4.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123884	SCV002551052	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580272	SCV002651229	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031256	SCV004016765	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492310	SCV004240284	likely benign	Breast and/or ovarian cancer	2023-03-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031256	SCV000053860	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-04-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031256	SCV000145619	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000031256	SCV000301428	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586208	SCV000591281	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA1 c.548-17G>T variant was identified in ClinVar (Bengin. Classified as benign by ENIGMA, Prevention Genetics, Invitae, Counsyl, ARUP Laboratories, Integrated Genetics, GeneDx, Centre for Mendelian Genomics at University Medical Centre Ljubljana, SCRP. Classified as likely benign by Department of Medical Genetics at University Hospital North Norway, COGR. Classified as VUS by BIC). The variant was identified in dnSNP (rs80358014). The variant has been reporting as co-occuring with pathogenic variants (BRCA1, c.2722G>T and BRCA2 variants, c.8237_8238delCA (p.Thr2736SerfsX17), c.2930_2940del and c.1202C>A (p.Ser401X), SCV000699264.1). The variant was identified in control databases in 59 of 280930 chromosomes (0 homozygous) at a frequency of 0.0002100 and was observed at the highest frequency in the European (non-Finnish) population in 47 of 128348 chromosomes (freq: 0.0003662) (Genome Aggregation Database March 6, 2019, v2.1.1).The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. 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	RCV000123884	SCV001906009	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000123884	SCV001959839	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000123884	SCV001965622	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000123884	SCV002034200	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031256	SCV004244161	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing