Submissions for variant NM_006939.4(SOS2):c.3769A>G (p.Asn1257Asp)

gnomAD frequency: 0.00020  dbSNP: rs150393358

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000652815	SCV000774687	likely benign	Noonan syndrome 9	2024-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805782	SCV002051284	likely benign	not specified	2024-09-09	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.3769A>G (p.Asn1257Asp) results in a conservative amino acid change in 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 0.00016 in 251484 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 132 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome phenotype (2.5e-06). c.3769A>G has been reported in the literature in at least an individual affected with Noonan Syndrome (example: Cordeddu_2015). This report however, does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26173643, 27920155). ClinVar contains an entry for this variant (Variation ID: 542399). Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV000652815	SCV002762976	likely benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003392500	SCV004134074	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	SOS2: BP4
PreventionGenetics, part of Exact Sciences	RCV003918081	SCV004735446	likely benign	SOS2-related disorder	2022-10-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).