ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.68T>A (p.Met23Lys) (rs746778122)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000702844 SCV000831715 uncertain significance Rasopathy 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with lysine at codon 23 of the BRAF protein (p.Met23Lys). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and lysine. While this variant is present in population databases (rs746778122), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with BRAF-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000779849 SCV000916702 benign not specified 2018-09-02 criteria provided, single submitter clinical testing Variant summary: BRAF c.68T>A (p.Met23Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function (Mutation Taster not included due to low p-value). The variant allele was found at a frequency of 8.3e-05 in 121194 control chromosomes, predominantly at a frequency of 0.00045 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 180-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.68T>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.

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