ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4813T>C (p.Leu1605=) (rs80356833)

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Total submissions: 10
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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) RCV000112405 SCV000578453 likely benign Breast-ovarian cancer, familial 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;
Invitae RCV001086469 SCV000076679 benign Hereditary breast and ovarian cancer syndrome 2020-11-30 criteria provided, single submitter clinical testing
GeneDx RCV000048666 SCV000167312 benign not specified 2014-04-04 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 RCV000131500 SCV000186489 benign Hereditary cancer-predisposing syndrome 2014-07-08 criteria provided, single submitter clinical testing This alteration is classified as 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.
Color Health, Inc RCV000131500 SCV000683218 likely benign Hereditary cancer-predisposing syndrome 2016-10-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048666 SCV000699176 likely benign not specified 2019-11-17 criteria provided, single submitter clinical testing
Counsyl RCV000112405 SCV000785399 likely benign Breast-ovarian cancer, familial 1 2017-07-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587240 SCV000888931 benign not provided 2018-08-24 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112405 SCV000145187 uncertain significance Breast-ovarian cancer, familial 1 2000-01-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354306 SCV001548891 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Leu1605= variant was identified in dbSNP (rs80356833) as “With Uncertain Significance allele”, ClinVar (3x as Benign by Invitae, GeneDx and Ambry and 1x as uncertain significance by BIC), in Clinvitae (4x as reported by ClinVar) and in the BRCA Share database UMD (6x as an unknown variant including 1x identified as co-occurring with the pathogenic BRCA1 c.5266dup, p.Gln1756ProfsX74 variant). The variant was identified in various control databases including the 1000 Genomes Project in 1 of 5000 (freq. 0.0002), the NHLBI Exome Sequencing Project in 3 of 4406 African American chromosomes (freq. 0.0007) and in Exome Aggregation Consortium (August 8th 2016) in 11 of 121406 chromosomes (freq. 0.00009) in the following populations: African in 8 of 10406 chromosomes (freq. 0.0007), South Asian in 1 of 16512 chromosomes (freq. 0.00006), and European (Non-Finnish) in 2 of 66738 chromosomes (freq. 0.00003), but was not seen in East Asian, Finnish, Latino and Other populations. The variant was not identified in GeneInsight COGR, COSMIC, MutDB, ARUP Laboratories BRCA Mutations Database, and the Fanconi Anemia Mutation Database. The p.Leu1605= 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.

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