Submissions for variant NM_007294.4(BRCA1):c.2232T>C (p.Ala744=)

dbSNP: rs4986846

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111804	SCV000577995	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 0.0015 (African), derived from ExAC (2014-12-17).
Invitae	RCV001084958	SCV000075781	benign	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162518	SCV000212912	likely benign	Hereditary cancer-predisposing syndrome	2014-06-03	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.
Counsyl	RCV000111804	SCV000488498	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000467834	SCV000540984	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162518	SCV000688376	likely benign	Hereditary cancer-predisposing syndrome	2016-05-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589539	SCV000698931	benign	not provided	2016-03-16	criteria provided, single submitter	clinical testing	Variant summary: The c.2232T>C variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 17/121360 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0001401. The variant was predominantly found in African sub-cohort with an allele frequency of 0.00153 (16/10398 chromosomes) which significantly exceeds the maximal expected frequency of a pathogenic allele (0.0010005) in this gene indicating that the variant is a benign polymorphism found in African population. The variant has been classified as a benign/likely benign by multiple clinical laboratories. Taken together, this variant has been classified as Benign.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001084958	SCV002025985	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162518	SCV002538105	likely benign	Hereditary cancer-predisposing syndrome	2022-01-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000503559	SCV004026791	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111804	SCV000144350	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1998-11-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503559	SCV000591373	benign	not specified		no assertion criteria provided	clinical testing	The p.Ala744Ala variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, and is also listed in the dbSNP database as coming from a "clinical source" (rs4986846) with a MAF score of 0.001, being identified in varying frequencies in various ethnic groups from the HapMap project. It was also reported in 2/111446 proband chromosomes of individuals from HBOC families, and classified as a polymorphism in the study by Myriad; although no control chromosomes were tested to establish the variant’s frequency in the general population (Judkins_2005, Miolo_2009). In addition, the variant was also identified in the UMD (x2), Exome Server and BOCs databases. In summary, based on the above information, the variant is classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000503559	SCV002036415	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589539	SCV002037857	likely benign	not provided		no assertion criteria provided	clinical testing