Submissions for variant NM_006939.4(SOS2):c.2854G>A (p.Asp952Asn)

gnomAD frequency: 0.00034  dbSNP: rs200387871

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000652821	SCV000774693	likely benign	Noonan syndrome 9	2024-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193657	SCV001362636	benign	not specified	2021-04-08	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.2854G>A (p.Asp952Asn) results in a conservative amino acid change located in the Ras guanine-nucleotide exchange factors catalytic domain (IPR001895) 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 0.00032 in 227036 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 480-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 Latino origin. c.2854G>A has been reported in the literature in an individual affected with RASopathy disorder and was described by the authors as "Likely disease-unrelated" (Cordeddu_2015), while it was also detected in another RASopathy-like sample co-occurring with a pathogenic variant (RAF1 c.770C>T, p.Ser257Leu; Castellanos_2020). Furthermore, the variant was detected in a case with metachondromatosis (Bowen_2011) and it was also detected in unaffected controls without Noonan Syndrome phenotype (Yamamoto_2015). These reports do not support 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. A ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813537	SCV002060669	benign	Noonan syndrome and Noonan-related syndrome	2020-09-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002440369	SCV002749901	benign	Cardiovascular phenotype	2019-11-20	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	RCV000652821	SCV002763023	benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003403501	SCV004134078	benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	SOS2: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003965406	SCV004794930	likely benign	SOS2-related disorder	2021-03-26	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).