ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.3378A>C (p.Glu1126Asp)

gnomAD frequency: 0.00076  dbSNP: rs145855459
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212334 SCV000150065 likely benign not specified 2017-10-19 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 RCV000116156 SCV000172958 likely benign Hereditary cancer-predisposing syndrome 2019-02-09 criteria provided, single submitter clinical testing in silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV001080937 SCV000253629 benign Familial cancer of breast; Fanconi anemia complementation group J 2021-12-17 criteria provided, single submitter clinical testing
Counsyl RCV000410562 SCV000489879 uncertain significance Fanconi anemia complementation group J 2016-07-06 criteria provided, single submitter clinical testing
Counsyl RCV000411633 SCV000489880 uncertain significance Neoplasm of ovary 2016-07-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587193 SCV000699720 benign not provided 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.3378A>C (p.Glu1126Asp) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant . This variant was found in 26/121034 control chromosomes (1 homozygote), predominantly observed in the African subpopulation at a frequency of 0.002549 (26/10200). This frequency is about 41 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance and another lab classified this variant as likely benign, all without evidence to independently evaluate. One internal sample also carried a pathogenic variant in RAD51C gene, further supporting the benign classification of the variant of interest. Taken together, this variant is classified as benign.
Color Diagnostics, LLC DBA Color Health RCV000116156 SCV000910768 benign Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587193 SCV001134025 likely benign not provided 2020-08-02 criteria provided, single submitter clinical testing
Mendelics RCV000989979 SCV001140741 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212334 SCV002072410 likely benign not specified 2019-05-06 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000116156 SCV002533689 benign Hereditary cancer-predisposing syndrome 2021-03-10 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354736 SCV001549423 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRIP1 p.Glu1126Asp variant was identified in 5 of 29146 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer or Lynch syndrome and was not identified in 10484 control chromosomes from healthy individuals (Easton 2016, Rodriquez-Flores 2014, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs145855459) as "With Uncertain significance allele", ClinVar (classified as benign by Integrated Genetics/Laboratory Corporation of America; as likely benign by Invitae, Ambry Genetics, and GeneDx; and as uncertain significance by two submitters), and the Zhejiang University Database (1x). The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 70 of 276548 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 69 of 24024 chromosomes (freq: 0.003) and Latino in 1 of 34412 chromosomes (freq: 0.00003), while the variant was not observed in the Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu1126 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000116156 SCV001977036 benign Hereditary cancer-predisposing syndrome 2021-09-27 no assertion criteria provided clinical testing

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