Submissions for variant NM_007294.4(BRCA1):c.5274A>G (p.Arg1758=)

gnomAD frequency: 0.00002  dbSNP: rs758739620

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495325	SCV000578356	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics	RCV000219833	SCV000277032	likely benign	Hereditary cancer-predisposing syndrome	2015-07-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000438514	SCV000512317	likely benign	not specified	2017-11-15	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.
Invitae	RCV000474379	SCV000560237	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219833	SCV000683278	likely benign	Hereditary cancer-predisposing syndrome	2016-07-12	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769709	SCV000901128	likely benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353703	SCV000591602	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Arg1758= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, UMD-LSDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was also identified in dbSNP (ID: rs758739620) as With Likely benign allele, ClinVar (classified as likely benign by Color Genomics, Ambry Genetics, GeneDx, Invitae, Enigma), Clinvitae, GeneInsight-COGR), databases. The variant was identified in control databases in 4 of 246272 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 4 of 111720 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg1758= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in 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.
Brotman Baty Institute, University of Washington	RCV000495325	SCV001242508	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro