ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.584T>C (p.Leu195Pro)

gnomAD frequency: 0.00197  dbSNP: rs4988347
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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120407 SCV000150071 benign not specified 2017-12-21 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.
Invitae RCV001082551 SCV000166684 benign Familial cancer of breast; Fanconi anemia complementation group J 2021-12-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000116162 SCV000172953 benign Hereditary cancer-predisposing syndrome 2017-12-08 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);No disease association in appropriately sized case-control study(ies);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;Subpopulation frequency in support of benign classification
Counsyl RCV000410203 SCV000489853 likely benign Fanconi anemia complementation group J 2016-07-05 criteria provided, single submitter clinical testing
Counsyl RCV000411259 SCV000489854 likely benign Neoplasm of ovary 2016-07-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589840 SCV000699730 benign not provided 2016-02-08 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000589840 SCV000807154 likely benign not provided 2017-08-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589840 SCV000889221 benign not provided 2021-03-11 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000116162 SCV000910543 likely benign Hereditary cancer-predisposing syndrome 2014-12-29 criteria provided, single submitter clinical testing
Mendelics RCV000990029 SCV001140793 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000410203 SCV001157291 benign Fanconi anemia complementation group J 2019-01-29 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000410203 SCV001287318 benign 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798361 SCV002043640 likely benign Breast and/or ovarian cancer 2019-12-05 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000120407 SCV002066143 likely benign not specified 2021-10-01 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000116162 SCV002533721 benign Hereditary cancer-predisposing syndrome 2021-03-12 criteria provided, single submitter curation
ITMI RCV000120407 SCV000084559 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000589840 SCV001550148 likely benign not provided no assertion criteria provided clinical testing The BRIP1 p.Leu195Pro variant was identified in 21 of 13772 proband chromosomes (frequency: 0.002) from individuals or families with prostate cancer, breast cancer, ovarian cancer, and Lynch syndrome and was present in 19 of 21561 control chromosomes (frequency: 0.0009) from healthy individuals (Bodian 2014, Kote-Jarai 2009, Kuusisto 2011, Lewis 2005, Rafnar 2011, Ramus 2015, Ray 2009, Rutter 2003, Seal 2006, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs4988347) as "With Likely benign allele", ClinVar (4x benign, 3x likely benign), Clinvitae, and the Zhejiang Colon Cancer Database (6x, likely neutral). The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 537 of 277082 chromosomes (2 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 8 of 24028 chromosomes (freq: 0.0003), Other in 10 of 6464 chromosomes (freq: 0.002), Latino in 24 of 34414 chromosomes (freq: 0.0007), European in 255 of 126622 chromosomes (freq: 0.002), Finnish in 226 of 25772 chromosomes (freq: 0.009), and South Asian in 14 of 30782 chromosomes (freq: 0.0005). The variant was not observed in the Ashkenazi Jewish or East Asian populations. A study by Lewis 2005 utilizing in silico bioinformatic tools predicted this variant may affect mRNA folding and exonic splicing enhancers. However, the same study showed that the variant did not segregate with disease in a family with breast cancer (Lewis 2005). The p.Leu195 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000589840 SCV001807087 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000589840 SCV001906038 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000589840 SCV001960027 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000589840 SCV001964912 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000120407 SCV002551206 likely benign not specified 2022-01-04 no assertion criteria provided clinical testing

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