Submissions for variant NM_005633.3(SOS1):c.2511-9dup

dbSNP: rs727503436

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151920	SCV000200441	likely benign	not specified	2013-09-11	criteria provided, single submitter	clinical testing	2511-9_2511-8insT in intron 15 of SOS1: This variant is not expected to have cli nical significance because it is not located in the conserved region of the spli cing consensus sequence. In addition, it has been identified in 0.097% (8/8246) of European American chromosomes and 0.21% (9/4256) of African American chromoso mes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS).
Eurofins Ntd Llc (ga)	RCV000680630	SCV000337447	uncertain significance	not provided	2015-11-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000680630	SCV000808074	likely benign	not provided	2020-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151920	SCV001448453	benign	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.2511-9dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 238074 control chromosomes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome phenotype (3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2511-9dupT in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV001453705	SCV001657403	likely benign	RASopathy	2022-10-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895042	SCV004715126	likely benign	SOS1-related condition	2022-04-28	criteria provided, single submitter	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).