ClinVar Miner

Submissions for variant NM_030662.4(MAP2K2):c.1140C>T (p.Ala380=) (rs146618055)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000521790 SCV000616562 likely benign Rasopathy 2017-05-09 reviewed by expert panel curation The filtering allele frequency of the c.1140C>T (p.Ala380=) variant in the MAP2K2 gene is 0.003% (2/796) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000043643 SCV000063156 likely benign not specified 2012-10-18 criteria provided, single submitter clinical testing Ala380Ala in exon 11 of MAP2K2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located ne ar a splice junction. In addition, this variant was identified via high-throughp ut sequencing in controls (MAF<1%) and presumed to be benign (Kelleher 2012).
GeneDx RCV000043643 SCV000207953 benign not specified 2014-08-26 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 RCV000521790 SCV001000776 benign Rasopathy 2020-11-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000043643 SCV001363490 benign not specified 2019-03-18 criteria provided, single submitter clinical testing Variant summary: MAP2K2 c.1140C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 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 0.00023 in 192890 control chromosomes. The observed variant frequency is approximately 93 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1140C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One expert panel has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Two other labs in ClinVar classified the variant as benign and likely benign respectively in 2014. Based on the evidence outlined above, the variant was classified as benign.

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