Submissions for variant NM_002755.4(MAP2K1):c.1068+12_1068+15del

dbSNP: rs397516788

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000157994	SCV000616558	benign	RASopathy	2017-05-09	reviewed by expert panel	curation	The filtering allele frequency of the c.1068+12_1068+15delTATT variant in the MAP2K1 gene is 0.285% (214/66740) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037588	SCV000061246	likely benign	not specified	2015-08-28	criteria provided, single submitter	clinical testing	c.1068+12_1068+15delTATT in intron 10 of MAP2K1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0 .3% (214/66740) of European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org).
GeneDx	RCV000157994	SCV000207929	benign	RASopathy	2012-08-21	criteria provided, single submitter	clinical testing	The variant is found in NOONAN panel(s).
PreventionGenetics, part of Exact Sciences	RCV000037588	SCV000309170	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000296799	SCV000393417	uncertain significance	Noonan syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000349253	SCV000393418	uncertain significance	Cardio-facio-cutaneous syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000157994	SCV000556849	benign	RASopathy	2025-02-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037588	SCV001360551	benign	not specified	2019-10-08	criteria provided, single submitter	clinical testing	Variant summary: MAP2K1 c.1068+12_1068+15delTATT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 0.0022 in 251462 control chromosomes, predominantly at a frequency of 0.0036 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1440 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K1 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. To our knowledge, no occurrence of c.1068+12_1068+15delTATT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions including an expert panel, ClinGen, (evaluation after 2014) cite the variant three times as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000296799	SCV001439178	benign	Noonan syndrome	2020-09-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001727530	SCV001477697	likely benign	not provided	2022-02-08	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813321	SCV002060553	benign	Noonan syndrome and Noonan-related syndrome	2020-07-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001727530	SCV003917399	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ENSG00000261351: BS2; MAP2K1: BS2
Clinical Genetics, Academic Medical Center	RCV000037588	SCV001924743	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001727530	SCV001974405	likely benign	not provided		no assertion criteria provided	clinical testing