Submissions for variant NM_006939.4(SOS2):c.2959-20T>C

gnomAD frequency: 0.00041  dbSNP: rs375042033

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251413	SCV001427003	benign	not specified	2020-07-27	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.2959-20T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 0.00013 in 229644 control chromosomes, predominantly at a frequency of 0.0013 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 520 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2959-20T>C in individuals affected with Noonan Syndrome 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002069328	SCV002432981	benign	Noonan syndrome 9	2025-01-29	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002069328	SCV002763018	benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing