Submissions for variant NM_006939.4(SOS2):c.3076C>T (p.Pro1026Ser)

gnomAD frequency: 0.00004  dbSNP: rs201874067

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681418	SCV000808881	uncertain significance	not provided	2018-07-20	criteria provided, single submitter	clinical testing	The P1026S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P1026S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P1026S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058885	SCV001223483	uncertain significance	Noonan syndrome 9	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1026 of the SOS2 protein (p.Pro1026Ser). This variant is present in population databases (rs201874067, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SOS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 561959). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001058885	SCV002763009	uncertain significance	Noonan syndrome 9		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003303104	SCV003997555	uncertain significance	Cardiovascular phenotype	2024-10-22	criteria provided, single submitter	clinical testing	The c.3076C>T (p.P1026S) alteration is located in exon 20 (coding exon 20) of the SOS2 gene. This alteration results from a C to T substitution at nucleotide position 3076, causing the proline (P) at amino acid position 1026 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003392518	SCV004120379	uncertain significance	SOS2-related disorder	2022-11-22	criteria provided, single submitter	clinical testing	The SOS2 c.3076C>T variant is predicted to result in the amino acid substitution p.Pro1026Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-50597480-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987662	SCV004803601	likely benign	not specified	2024-01-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000681418	SCV005433766	uncertain significance	not provided	2024-10-01	criteria provided, single submitter	clinical testing