ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.2440C>T (p.Arg814Cys) (rs201869624)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131535 SCV000186530 likely benign Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing No disease association in small case-control study
GeneDx RCV000120399 SCV000210818 likely benign not specified 2017-10-20 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 RCV001083712 SCV000219093 benign Familial cancer of breast; Fanconi anemia, complementation group J 2020-12-07 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120399 SCV000593773 uncertain significance not specified 2016-06-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588835 SCV000699695 likely benign not provided 2016-12-09 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.2440C>T (p.Arg814Cys) variant located in the P-loop containing nucleoside triphosphate hydrolase and ATP-dependent helicase, C-terminal domains (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 58/120652 (1/2080), predominantly in the East Asian cohort, 47/8492 (1/180), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. Therefore, suggesting the variant is a common polymorphism found in population(s) of East Asian origin. The variant of interest has been reported in multiple affected individuals via publications as a germline and somatic mutation. In addition multiple clinical diagnostic laboratories cite the variant with conflicting classifications of "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "Likely Benign."
Counsyl RCV000662392 SCV000784805 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2016-12-14 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131535 SCV000821960 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000709540 SCV000839367 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131535 SCV000902641 likely benign Hereditary cancer-predisposing syndrome 2015-04-27 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030535 SCV001193531 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
ITMI RCV000120399 SCV000084551 not provided not specified 2013-09-19 no assertion provided reference population
Leiden Open Variation Database RCV000588835 SCV001364475 uncertain significance not provided 2019-08-13 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356698 SCV001551939 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRIP1 p.Arg814Cys variant was identified in 3 of 1382 proband chromosomes (frequency: 0.002) from individuals or families with breast, colorectal cancer (Lin 2016, Ng 2016, Pearlman 2016). The variant was also identified in dbSNP (ID: rs201869624) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx; classified as likely benign by Invitae), Clinvitae (classified as uncertain significance by ClinVar, Invitae). The variant was not identified in the Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 117 of 276074 chromosomes at a frequency of 0.000424 in east Asian and south Asian populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg814 residue is 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 1 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. This variant is classified as a variant of uncertain significance.

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