Submissions for variant NM_006939.4(SOS2):c.3250A>G (p.Thr1084Ala)

gnomAD frequency: 0.00045  dbSNP: rs150752193

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000652827	SCV000774699	likely benign	Noonan syndrome 9	2025-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174921	SCV001338357	likely benign	not specified	2022-03-21	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.3250A>G (p.Thr1084Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 251436 control chromosomes (gnomAD). The observed variant frequency is approximately 135 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. c.3250A>G has been reported in the literature in an individual under the age of 18 who went through WES for cancer related genes (Chan_2018). Authors classified the variant VUS. This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002325312	SCV002611282	likely benign	Cardiovascular phenotype	2022-10-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome-Nilou Lab	RCV000652827	SCV002763007	likely benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003928135	SCV004754932	benign	SOS2-related disorder	2024-03-05	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).