ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2232T>C (p.Ala744=) (rs4986846)

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Total submissions: 9
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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 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 and ovarian cancer syndrome 2020-12-07 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 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 Health, Inc 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111804 SCV000144350 uncertain significance Breast-ovarian cancer, familial 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.

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