BRAF NM_001354609.1:c.622A>G, Ile208Val

Variant summary: BRAF c.622A>G (p.Ile208Val) results in a conservative amino acid change located in the Raf-like Ras-binding domain (IPR003116) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251166 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.622A>G has been reported in the literature in unaffected individuals and index cases with clinical features inconsistent with a RASopathy in families undergoing evaluation for Noonan Syndrome and Related Conditions (Grant_2018). The variant was also identified in the paternal specimen following its initial identification in a prenatal specimen undergoing evaluation for Noonan syndrome and Related conditions at our laboratory. These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. Co-occurrences with other pathogenic variant(s) have been reported in a melanoma cell line ( BRAF c.1799T>A, p.Val600Glu), providing supporting evidence for a benign role (Ikediobi_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

We observed the Ile208Val variant in BRAF in one individual with middle aortic s yndrome, low nasal bridge, hypertension, facial coarseness, short stature, learn ing disabilities/mental retardation, wide-spaced nipples and webbed neck and her reportedly unaffected parent, both tested by our laboratory. The variant was al so found in a fetus with increased nuchal translucency and her unaffected father (personal communication with the mother via our ClinVar entry). GeneDx observed the variant in three unrelated families undergoing exome testing in which the c linical presentations of individuals with the variant (n=6) were either normal o r had clinical features inconsistent with a RASopathy. This variant has also bee n found in the general population at a frequency of 3/276842 alleles (gnomAD, rs 727504571). Ile208Val has been reported in a melanoma cell line which also carri ed Val600Glu, a well-characterized activating mutation (Ikediobi 2006). Computat ional analyses (biochemical amino acid properties, conservation, AlignGVGD, Poly Phen2, and SIFT) do not provide strong support for or against an impact to the n ormal function of the protein. In summary, based upon the 3 observations in the general population and the 8 observations in individuals without a RASopathy dia gnosis, this variant is likely benign (Grant 2018). ACMG/AMP criteria applied: B S1_Supporting, BS2