ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2208A>G (p.Ala736=) (rs144984153)

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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) RCV000495330 SCV000578874 likely benign Breast-ovarian cancer, familial 2 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;
GeneDx RCV000123950 SCV000167340 benign not specified 2014-02-21 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.
Ambry Genetics RCV000163357 SCV000213891 likely benign Hereditary cancer-predisposing syndrome 2014-07-31 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.
Invitae RCV001083753 SCV000253000 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000123950 SCV000602795 benign not specified 2015-08-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163357 SCV000683471 likely benign Hereditary cancer-predisposing syndrome 2015-10-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000195503 SCV001133702 likely benign not provided 2019-11-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123950 SCV001338309 likely benign not specified 2020-02-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353979 SCV000591793 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ala736= variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in the following databases: dbSNP (ID: rs144984153) as “With Likely benign allele”, ClinVar (4x, as likely benign by Enigma, Ambry Genetics, Invitae and as benign by GeneDx), Clinvitae (3x, as likely benign and benign), UMD-LSDB (3x records, as 3-UV). The variant was identified in control databases in 17 of 277040 chromosomes at a frequency of 0.000061 in the following populations: African in 16 of 24026 chromosomes (freq. 0.00066), Latino in 1 of 34360 chromosomes (freq. 0.00003), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Ala736= variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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.

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