ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.430G>A (p.Ala144Thr) (rs116952709)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120404 SCV000167435 benign not specified 2013-12-31 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 RCV000131536 SCV000186531 benign Hereditary cancer-predisposing syndrome 2014-08-08 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV001084094 SCV000218946 benign Familial cancer of breast; Fanconi anemia, complementation group J 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000408974 SCV000489861 benign Fanconi anemia, complementation group J 2016-08-15 criteria provided, single submitter clinical testing
Counsyl RCV000410510 SCV000489862 benign Neoplasm of ovary 2016-08-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120404 SCV000600922 benign not specified 2017-02-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131536 SCV000684280 benign Hereditary cancer-predisposing syndrome 2015-04-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589730 SCV000699727 benign not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.430G>A (p.Ala144Thr) 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 164/121364 control chromosomes (2 homozygotes) at a frequency of 0.0013513, which is approximately 22 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589730 SCV000889216 benign not provided 2017-02-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286074 SCV001472597 likely benign none provided 2019-09-04 criteria provided, single submitter clinical testing
ITMI RCV000120404 SCV000084556 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000131536 SCV000787970 likely benign Hereditary cancer-predisposing syndrome 2017-10-26 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000120404 SCV001364459 benign not specified 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 RCV001355323 SCV001550181 benign Carcinoma of colon no assertion criteria provided clinical testing The BRIP1 p.Ala144Thr variant was identified in 7 of 3854 proband chromosomes (frequency: 0.002) from Australian, Korean, Chinese and America individuals or families with suspected Lynch Syndrome, or BRCA1/2 negative familial breast cancer, but was not identified in 186 control chromosomes (Yurgelun 2015, Lewis 2005, Kim 2016 , Cao 2009). In one study, the variant cooccurred with BRIP1 c.3401delC, and both variants were not found to segregate with breast cancer, being inherited from the father of the index case who had no personal or family history of breast cancer, and not from the affected mother with a strong family history (Lewis 2005 ). The variant was identified in ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Counsyl; likely benign by Illumina; and classification not provided by ITMI), Clinvitae ( classified as benign 5X, and likely benign 1X), Cosmic (1X in a bladder carcinoma, confirmed as somatic), and the Zhejiang Colon Cancer Database (3X); and was not identified in MutDB. The variant was also identified in control databases in 390 (2 homozygous) of 277018 chromosomes at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following population at a frequency greater than 1%: East Asian in 361 of 18862 chromosomes (freq: 0.019). The p.Ala144Thr residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000120404 SCV001905916 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000120404 SCV001956580 benign not specified no assertion criteria provided clinical testing

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