Submissions for variant NM_007294.4(BRCA1):c.21C>T (p.Arg7=)

gnomAD frequency: 0.00165  dbSNP: rs149402012

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000169370	SCV000577993	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0053 (African), derived from ExAC (2014-12-17).
GeneDx	RCV000168476	SCV000167223	benign	not specified	2014-01-15	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.
Eurofins Ntd Llc (ga)	RCV000168476	SCV000202278	benign	not specified	2014-12-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163211	SCV000213734	likely benign	Hereditary cancer-predisposing syndrome	2014-09-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768582	SCV000219179	benign	Breast and/or ovarian cancer	2017-01-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000169370	SCV000220746	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-09-26	criteria provided, single submitter	literature only
Invitae	RCV001079978	SCV000252813	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000458876	SCV000540977	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168476	SCV000593665	benign	not specified	2021-10-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163211	SCV000683019	benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656648	SCV000885078	benign	not provided	2022-03-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000169370	SCV001287538	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001079978	SCV002026052	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001079978	SCV002515109	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000163211	SCV002538101	benign	Hereditary cancer-predisposing syndrome	2020-09-29	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004554707	SCV004719993	benign	BRCA1-related disorder	2019-04-10	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mayo Clinic Laboratories, Mayo Clinic	RCV000656648	SCV000778782	likely benign	not provided	2017-11-16	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000169370	SCV001237690	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357572	SCV001553078	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1, p.Arg7Arg variant was identified in 25 of 112686 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Fackenthal 2011, Houdayer 2012, Judkins 2005). The variant was also identified in dbSNP (ID: rs149402012) as “other”, Clinvitae database (uncertain significance by EmvClass, likely benign by ClinVar, benign by Invitae), ARUP COSMIC, the ClinVar database (uncertain significance by COG-CHEO, likely benign by Ambry Genetics and Counsyl, benign by GeneDx, Emory Genetics and Invitae), GeneInsight COGR database (uncertain significance by COG-CHEO, likely benign by COG-NYG, benign by LMM), UMD (56X with a “likely neutral” classification). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.4484G>T, p.Arg1495Met), increasing the likelihood that the p.Arg7Arg variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002), NHLBI GO Exome Sequencing Project in 22 of 4404 African American alleles, Exome Aggregation Consortium database (August 8, 2016) in 63 (1 homozygous) of 120800 chromosomes (freq. 0.0005) in the following populations: African in 59 of 10322 chromosomes (freq. 0.006), and Latino in 4 of 11516 chromosomes (freq. 0.0003), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Arg7Arg 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, 1 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	RCV000168476	SCV001905816	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656648	SCV001965454	likely benign	not provided		no assertion criteria provided	clinical testing