ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1933A>G (p.Met645Val) (rs146051850)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000680336 SCV000884239 benign not provided 2017-11-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130724 SCV000185611 benign Hereditary cancer-predisposing syndrome 2015-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown),Subpopulation frequency in support of benign classification
GeneDx RCV000680336 SCV000521060 benign not provided 2018-04-11 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.
ITMI RCV000121627 SCV000085825 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000286004 SCV000401721 likely benign Neurofibromatosis-Noonan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000341061 SCV000401722 likely benign Café-au-lait macules with pulmonary stenosis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000206514 SCV000401723 likely benign Neurofibromatosis, type 1 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000301396 SCV000401724 likely benign Neurofibromatosis, familial spinal 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121627 SCV000917896 benign not specified 2018-12-27 criteria provided, single submitter clinical testing Variant summary: NF1 c.1933A>G (p.Met645Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 301926 control chromosomes (gnomAD and publication), predominantly at a frequency of 0.017 within the East Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 81.59 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1933A>G has been reported in the literature in individuals affected with Neurofibromatosis Type 1 and male breast cancer without strong evidence for causality while, two of the studies report co-occurrence of the variant with other causative variants (c.3211G>C; c.910C>T (classified pathogenic in ClinVar); c.162_163insAT; other nonsense mutations) (Momozawa_2018, Pasmant_2015, Zhang_2015, Xu_2014, Ko_2013). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (3x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000206514 SCV000261408 benign Neurofibromatosis, type 1 2018-01-12 criteria provided, single submitter clinical testing

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