Submissions for variant NM_006939.4(SOS2):c.3952C>T (p.Pro1318Ser)

gnomAD frequency: 0.00029  dbSNP: rs140995728

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000555942	SCV000656031	likely benign	Noonan syndrome 9	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175493	SCV001339086	benign	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.3952C>T (p.Pro1318Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 251440 control chromosomes, predominantly at a frequency of 0.00095 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 380 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3952C>T has been reported in the literature in an individual affected with Noonan Syndrome and Related Conditions, without strong evidence for causality (Cordeddu_2015). 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. The following publication has been ascertained in the context of this evaluation (PMID: 26173643). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001644664	SCV001856913	benign	not provided	2020-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002358610	SCV002621043	benign	Cardiovascular phenotype	2019-01-09	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000555942	SCV002762964	benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001644664	SCV004134072	benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	SOS2: BP4, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003962607	SCV004782014	benign	SOS2-related disorder	2020-09-30	criteria provided, single submitter	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).