Submissions for variant NM_004333.6(BRAF):c.622A>G (p.Ile208Val)

gnomAD frequency: 0.00003  dbSNP: rs727504571

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV001172270	SCV001335308	uncertain significance	RASopathy	2020-03-09	reviewed by expert panel	curation	The c.622A>G (p.Ile208Val) variant in BRAF is present in 0.00001% (2/128934) European alleles in gnomAD. This variant was observed in two healthy adult individuals who did not have clinical features of a RASopathy (SCV000205449.5; PMID:29945942). Additionally, 12 apparently unaffected parental samples were observed with this variant, however this evidence does not meet current scoring criteria for BS2 at this time (BS2 not met; SCV000329576.8, SCV001011557.1). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Ile208Val variant is uncertain at this time. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155739	SCV000205449	likely benign	not specified	2018-07-21	criteria provided, single submitter	clinical testing	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
GeneDx	RCV000589318	SCV000329576	likely benign	not provided	2019-02-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29945942)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155739	SCV000698344	likely benign	not specified	2019-09-06	criteria provided, single submitter	clinical testing	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.
Invitae	RCV001172270	SCV001596531	likely benign	RASopathy	2022-07-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813403	SCV002060719	uncertain significance	Noonan syndrome and Noonan-related syndrome	2019-11-21	criteria provided, single submitter	clinical testing