ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3197+9dup

dbSNP: rs755212937
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001080922 SCV000284429 benign Neurofibromatosis, type 1 2024-01-27 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV000249416 SCV000306253 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000680361 SCV000571396 likely benign not provided 2017-10-02 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.
Sema4, Sema4 RCV002257531 SCV002527493 likely benign Hereditary cancer-predisposing syndrome 2021-08-26 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000249416 SCV002555666 benign not specified 2022-06-06 criteria provided, single submitter clinical testing Variant summary: NF1 c.3197+9dupA alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00041 in 152128 control chromosomes (gnomAD v3.1, genomes dataset). However, the variant was found in the Amish subpopulation at a frequency of 0.044 (i.e. 40/912 alleles), including 2 homozygotes. This frequency is about 210-fold of the estimated maximum expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.001), suggesting that the variant is a benign polymorphism. c.3197+9dupA has been reported in the literature in individuals affected with various tumor phenotypes (examples: Schrader_2016, Henn_2019). However, in one of these reports a co-occurrence with another pathogenic variant has been reported (PTEN c.930_931delTA (p.Asp310Glufs*2) in Henn_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab RCV001080922 SCV002560639 likely benign Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV004558584 SCV005047821 likely benign Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2015-05-22 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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