ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2286T>C (p.Arg762=) (rs61754141)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212321 SCV000167432 benign not specified 2014-02-03 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 RCV000124023 SCV000213125 likely benign Hereditary cancer-predisposing syndrome 2014-06-23 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 RCV001079356 SCV000252875 benign Familial cancer of breast; Fanconi anemia, complementation group J 2020-12-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000410265 SCV000404597 likely benign Fanconi anemia, complementation group J 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.
Counsyl RCV000410265 SCV000489979 likely benign Fanconi anemia, complementation group J 2016-09-06 criteria provided, single submitter clinical testing
Counsyl RCV000411328 SCV000489980 likely benign Neoplasm of ovary 2016-09-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212321 SCV000593764 likely benign not specified 2015-09-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212321 SCV000600902 likely benign not specified 2017-05-10 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000124023 SCV000679728 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000124023 SCV000684203 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586863 SCV000699688 benign not provided 2016-03-07 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.2286T>C variant affects a conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts a damaging outcome for this variant. 3/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect ESE site of SF2/ASF (IgM-BRCA1). However, these predictions have not been confirmed by experimental studies. This variant is found in 61/121286 control chromosomes (1 homozygote) at a frequency of 0.0005029, which is about 8 times the maximal expected frequency of a pathogenic BRIP1 allele (0.0000625), suggesting this variant is benign. In addition, multiple clinical laboratories classified this variant as likely benign/benign. Taken together, this variant was classified as benign.
PreventionGenetics,PreventionGenetics RCV000212321 SCV000807132 benign not specified 2017-08-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586863 SCV000889213 benign not provided 2018-07-30 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358580 SCV001554361 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRIP1 p.Arg762= variant was identified in 1 of 188 proband chromosomes (frequency: 0.005) from individuals or families with prostate cancer (Ray 2009). The variant was also identified in the following databases, dbSNP (ID: rs61754141) as “With Uncertain significance allele”, ClinVar (7x, as benign by GeneDx, Invitae, as likely benign by Ambry Genetics, Counsyl, as uncertain significance by Illumina), Clinvitae (6x, with conflicting predictions as benign, likely benign and uncertain significance), Zhejiang Colon Cancer Database (1x with unknown pathogenicity). The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 179 of 276976 (1 homozygous) chromosomes at a frequency of 0.0006 in the following populations: African in 129 of 24038 (1 homozygous) chromosomes (freq. 0.005), other in 2 of 6462 chromosomes (freq. 0.0003), Latino in 25 of 34400 chromosomes (freq. 0.0007), European in 22 of 126538 chromosomes (freq. 0.0002), and South Asian in 1 of 30782 chromosomes (freq. 0.00003), increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The p.Arg762Arg 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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