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  • See Evidence submitted by expert panel for details.

CA296098

180895 (ClinVar)

Gene: MAP2K1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: daa41704-c6b0-4d20-8b22-57a3fc0ab2f1
Approved on: 2019-09-24
Published on: 2019-10-02

HGVS expressions

NM_002755.3:c.1068+9A>G
NM_006049.3:c.*967T>C
NR_138061.1:n.1486T>C
ENST00000307102.9:c.1068+9A>G
ENST00000566326.1:c.540+9A>G
NC_000015.10:g.66489772A>G
CM000677.2:g.66489772A>G
NC_000015.9:g.66782110A>G
CM000677.1:g.66782110A>G
NC_000015.8:g.64569164A>G
NG_008305.1:g.107900A>G
NG_051234.1:g.13044T>C
More

Likely Benign

Met criteria codes 2
BP7 BP4
Not Met criteria codes 6
PS4 PM2 PM1 BA1 BS1 BS2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
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.
Met criteria codes
BP7
Splicing is not predicted to be impacted by MaxEntScan. 6 other mammals in UCSC database have a G at this site.
BP4
No predicted impact to splicing. 6 other mammals in UCSC database have a G at this site.
Not Met criteria codes
PS4
Not met because of varying phenotypes of patients from these labs: Sema4: Identified in 1 fetus (CVS) enlarged NT, possibly cystic hygroma. Fetal echo revealed AV canal. Variant was inherited from presumably unaffected mother. However, fetus also had 1.14Mb deletion on 3q26.1 (via CVS – same sample, VUS; also maternally inherited). Array run on POC after miscarriage showed no array or chromosomal abnormalities. Invitae: Identified in 5 patients: -Male in 60's with dyslipidemia and infiltrative cardiomyopathy who ordered an exome. -Juvenile male with no indication who ordered a Noonan panel. -Female in 50's with no indication who ordered a hypertrophic cardiomyopathy panel. -Juvenile male who was 'affected' who ordered a comprehensive Rasopathy panel. -Female neonate with heterotaxy, pulmonary atresia, and right atrial isomerism who ordered a Congenital Heart Defects and Heterotaxy Panel LabCorp: Seen in a 35-year-old female undergoing testing on our NGS panel for Noonan and related conditions which included 9 genes (BRAF, HRAS, KRAS, MA2K1, MAP2K2, PTPN11, RAF1, SHOC2, and SOS1). No other pathogenic variants in any of the genes on the panel were identified.
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Does not occur in aa 43-61 or 124-134.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Not met, highest frequencies in Ashkenazi Jewish and "other". Next highest is in Latino alleles (MAF = 0.0002257).
BS2
Identified in 2 ostensibly healthy individuals in Illumina's TruGenome Predisposition Screen test, but these individuals were not well-phenotyped/not evaluated by a clinician and confirmed not to have RASopathies.
Curation History
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