ClinVar Miner

Submissions for variant NM_033360.4(KRAS):c.90C>T (p.Asp30=) (rs113623140)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000462133 SCV000616475 likely benign Rasopathy 2017-04-18 reviewed by expert panel curation The filtering allele frequency of the c.90C>T (p.Asp30=) variant in the KRAS gene is 0.0292% (5/6746) 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)
GeneDx RCV000126519 SCV000170026 benign not specified 2014-03-31 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.
Invitae RCV000462133 SCV000562256 likely benign Rasopathy 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000126519 SCV001363594 likely benign not specified 2019-05-13 criteria provided, single submitter clinical testing Variant summary: KRAS c.90C>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 0.0002 in 246426 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in KRAS causing Noonan Syndrome and Related Conditions phenotype (1.3e-05), strongly suggesting that the variant is benign. Moreover, the variant was found in certain subpopulations with even higher frequencies, e.g. it was reported at a frequency of 0.00044 within the East Asian subpopulation, where it was found in Koreans with an allele frequency of 0.0021 (i.e. 8/3812 alleles), further supporting a benign effect. c.90C>T has been reported in the literature in a Korean individual affected with colorectal cancer (Won 2017). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014), one from an expert panel (ClinGen) and a clinical diagnostic laboratory, cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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