Submissions for variant NM_002755.4(MAP2K1):c.1068+9A>G

gnomAD frequency: 0.00024  dbSNP: rs368800650

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV001030078	SCV001192869	likely benign	RASopathy	2019-09-24	reviewed by expert panel	curation	The c.1068+9A>G intronic variant in the MAP2K1 gene is classified as likely benign because it does not alter an amino acid residue, is not located within the canonical splice site, and computational splice prediction tools do not predict an impact on splicing (BP4, BP7). It has been identified in 0.01123% (lower bound of the 95% CI of 8/35440) of Latino chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). This variant has been observed in several individuals with varying clinical presentations that lack clear associations with a RASopathy. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied: BP4, BP7.
GeneDx	RCV001721005	SCV000207928	benign	not provided	2019-08-08	criteria provided, single submitter	clinical testing
Invitae	RCV001030078	SCV000776918	likely benign	RASopathy	2024-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000157993	SCV001363815	benign	not specified	2019-05-27	criteria provided, single submitter	clinical testing	Variant summary: MAP2K1 c.1068+9A>G 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 0.00031 in 251454 control chromosomes (gnomAD). The observed variant frequency is approximately 124 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 benign. To our knowledge, no occurrence of c.1068+9A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant once as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003895068	SCV004717117	benign	MAP2K1-related condition	2020-08-17	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).