ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.890A>G (p.Lys297Arg) (rs28997570)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120408 SCV000150076 likely benign not specified 2017-12-14 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.
Invitae RCV001084039 SCV000166690 benign Familial cancer of breast; Fanconi anemia, complementation group J 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000116167 SCV000183882 benign Hereditary cancer-predisposing syndrome 2014-06-24 criteria provided, single submitter clinical testing Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Counsyl RCV000412293 SCV000489849 likely benign Fanconi anemia, complementation group J 2016-08-12 criteria provided, single submitter clinical testing
Counsyl RCV000410013 SCV000489850 likely benign Neoplasm of ovary 2016-08-12 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000116167 SCV000576452 likely benign Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120408 SCV000593768 likely benign not specified 2016-01-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590718 SCV000699736 benign not provided 2016-01-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000590718 SCV000807158 likely benign not provided 2016-12-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000590718 SCV000885125 likely benign not provided 2017-10-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590718 SCV000889231 benign not provided 2019-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000116167 SCV000910553 likely benign Hereditary cancer-predisposing syndrome 2015-02-11 criteria provided, single submitter clinical testing
Mendelics RCV000990022 SCV001140785 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000412293 SCV001284959 uncertain significance Fanconi anemia, complementation group J 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV000412293 SCV001482649 uncertain significance Fanconi anemia, complementation group J 2020-09-18 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ITMI RCV000120408 SCV000084560 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354244 SCV001548807 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRIP1 p.Lys297Arg variant was identified in 67 of 35802 proband chromosomes (frequency: 0.002) from British, American and European individuals or families with breast, ovarian or familial prostate cancer and was present in 1 of 704 control chromosomes (frequency: 0.001) from healthy individuals (Easton 2016, Kote-Jarai 2009, Ramus 2015, Yurgelun 2015, Bodian 2014). The variant was identified in dbSNP (ID: rs28997570) “With other allele”, ClinVar (classified benign by Ambry Genetics, likely benign by Invitae, Counsyl, Institute for Biomarker Research (Medical Diagnostic Laboratories L.L.C), Genetic Services Laboratory (University of Chicago), Quest Diagnostics Nichols Institute San Juan Capistrano, and GeneDx, and classification not provided by ITMI), Clinvitae (5x), and Zhejiang Colon Cancer Database (7x, coocurring with a pathogenic BRIP1 variant (c.2392C>T/p,Arg798X). The variant was not identified in Cosmic and MutDB. The variant was also identified in control databases in 285 of 276594 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 10 of 24030 chromosomes (freq: 0.0004), Other in 6 of 6450 chromosomes (freq: 0.0009), Latino in 14 of 34408 chromosomes (freq: 0.0004), European Non-Finnish in 215 of 126148 chromosomes (freq: 0.002), European Finnish in 27 of 25788 chromosomes (freq: 0.001), and South Asian in 13 of 30770 chromosomes (freq: 0.0004), and was not observed in the Ashkenazi Jewish and East Asian populations. The p.Lys297 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood Arg impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000120408 SCV001808106 benign not specified no assertion criteria provided clinical testing

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