ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2220G>T (p.Gln740His) (rs45589637)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131414 SCV000186392 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000488342 SCV000575119 uncertain significance not provided 2017-01-31 criteria provided, single submitter clinical testing
Color RCV000131414 SCV000910572 likely benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Counsyl RCV000409608 SCV000489867 uncertain significance Fanconi anemia, complementation group J 2016-08-23 criteria provided, single submitter clinical testing
Counsyl RCV000411134 SCV000489868 uncertain significance Neoplasm of ovary 2016-08-23 criteria provided, single submitter clinical testing
GeneDx RCV000120396 SCV000210815 likely benign not specified 2017-12-13 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.
GeneKor MSA RCV000131414 SCV000821956 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120396 SCV000593775 uncertain significance not specified 2016-04-20 criteria provided, single submitter clinical testing
ITMI RCV000120396 SCV000084548 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000778128 SCV000914253 uncertain significance BRIP1-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing The BRIP1 c.2220G>T (p.Gln740His) missense variant has been reported in at least four studies in which it is found in a heterozygous state in total of three individuals with Lynch syndrome, one of whom also carried a homozygous variant in the MUTYH gene (Bodian et al. 2014; Ramus et al. 2015; Yurgelun et al. 2015; Easton et al. 2016). The p.Gln740His variant was identified in a heterozygous state in six of 3431 controls and is reported at a frequency of 0.00140 in the Latino population of the Genome Aggregation Database. Based on the limited evidence, the p.Gln740His variant is classified as a variant of unknown significance but suspicious for pathogenicity for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000488342 SCV000699683 likely benign not provided 2016-09-02 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.2220G>T (p.Gln740His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 58/133810 control chromosomes at a frequency of 0.0004335, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple cancer patients, however, a case-control study showed that this variant was not associated with breast cancer (OR=0.638, P=0.49, Haiman_2013). In addition, two patients carry the variant of interest and a pathogenic variant, homozygous MUTYH c.1187G>A/p.Gly396Asp and PALB2 c.3113G>A/W1038X, respectively (Yurgelun_2015, Kahn_2016), suggesting the variant of interest may be benign. On the other hand, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign.
Invitae RCV000123354 SCV000166677 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 740 of the BRIP1 protein (p.Gln740His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs45589637, ExAC 0.1%). This variant has been reported in individuals affected with ovarian cancer (PMID: 26315354), peritoneal cancer (PMID: 27547810), breast cancer (PMID: 25186627, 26534844, 26921362, 28202063), and in individuals undergoing testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 133752). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000409608 SCV000839371 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000488342 SCV000807127 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120396 SCV000600898 uncertain significance not specified 2017-07-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000488342 SCV000889209 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000131414 SCV000805252 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-09 no assertion criteria provided clinical testing

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