NM_012250.6(RRAS2):c.215A>T (p.Gln72Leu) AND Ovarian neoplasm

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 2, 1994
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001072115.1

Allele description [Variation Report for NM_012250.6(RRAS2):c.215A>T (p.Gln72Leu)]

NM_012250.6(RRAS2):c.215A>T (p.Gln72Leu)

Gene:
RRAS2:RAS related 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p15.2
Genomic location:
Preferred name:
NM_012250.6(RRAS2):c.215A>T (p.Gln72Leu)
Other names:
L72Q; NM_012250.6(RRAS2):c.215A>T; p.Gln72Leu
HGVS:
  • NC_000011.10:g.14294844T>A
  • NG_017058.1:g.74663A>T
  • NM_001102669.2:c.-17A>T
  • NM_001177314.2:c.110A>T
  • NM_001177315.1:c.-17A>T
  • NM_012250.6:c.215A>TMANE SELECT
  • NP_001170785.1:p.Gln37Leu
  • NP_036382.2:p.Gln72Leu
  • NC_000011.9:g.14316390T>A
  • NM_001177314.1:c.110A>T
  • NM_012250.5:c.215A>T
  • NM_012250.6:c.215A>T
Protein change:
Q37L; LEU72GLN
Links:
OMIM: 600098.0001; dbSNP: rs113954997
NCBI 1000 Genomes Browser:
rs113954997
Molecular consequence:
  • NM_001102669.2:c.-17A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001177315.1:c.-17A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001177314.2:c.110A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012250.6:c.215A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Ovarian neoplasm
Synonyms:
Neoplasm of ovary; Ovarian tumor; Ovarian Neoplasms
Identifiers:
MONDO: MONDO:0021068; MeSH: D010051; MedGen: C0919267; Human Phenotype Ontology: HP:0100615

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001237453OMIM
no assertion criteria provided
Pathogenic
(Aug 2, 1994) 		somaticliterature only

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedsomaticnot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome.

Capri Y, Flex E, Krumbach OHF, Carpentieri G, Cecchetti S, Lißewski C, Rezaei Adariani S, Schanze D, Brinkmann J, Piard J, Pantaleoni F, Lepri FR, Goh ES, Chong K, Stieglitz E, Meyer J, Kuechler A, Bramswig NC, Sacharow S, Strullu M, Vial Y, Vignal C, et al.

Am J Hum Genet. 2019 Jun 6;104(6):1223-1232. doi: 10.1016/j.ajhg.2019.04.013. Epub 2019 May 23.

PubMed [citation]
PMID:
31130282
PMCID:
PMC6562003

Germline-Activating RRAS2 Mutations Cause Noonan Syndrome.

Niihori T, Nagai K, Fujita A, Ohashi H, Okamoto N, Okada S, Harada A, Kihara H, Arbogast T, Funayama R, Shirota M, Nakayama K, Abe T, Inoue SI, Tsai IC, Matsumoto N, Davis EE, Katsanis N, Aoki Y.

Am J Hum Genet. 2019 Jun 6;104(6):1233-1240. doi: 10.1016/j.ajhg.2019.04.014. Epub 2019 May 23.

PubMed [citation]
PMID:
31130285
PMCID:
PMC6562005
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV001237453.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

Noonan Syndrome 12

In an Indian boy (patient 4) who died at age 2 weeks with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygosity for a de novo germline c.215A-T transversion (c.215A-T, NM_012250.5) in the RRAS2 gene, resulting in a gln72-to-leu (Q72L) substitution within the switch II region. The mutation was not present in general population genetic databases. Functional analysis in HEK293T cells showed constitutively enhanced ERK (see 601795) phosphorylation with the Q72L mutant compared to wildtype protein.

In a boy (patient HU1) with severe failure to thrive and features of Noonan syndrome, who died at age 3 years, Niihori et al. (2019) identified heterozygosity for the Q72L mutation (c.215A-T, NM_012250.6) in the RRAS2 gene. The mutation was shown to have arisen de novo. Functional analysis in HEK293T cells showed elevated association of RAF1 (164760) and activation of ERK1/2 (see 176948) and ELK1 (311040). Low-dose overexpression of the Q72L variant in zebrafish larvae resulted in a significantly increased ceratohyal angle compared to wildtype larvae; overexpression at higher dose caused lethal developmental impairments. Noting the severe phenotype present in patient HU1 compared to other RRAS2-mutated patients, as well as the more potent effects with the Q72L variant compared to other Noonan-associated RRAS2 variants in their in vitro and in vivo assays, the authors suggested a possible genotype/phenotype correlation.

Somatic Mutation in Ovarian Cancer

Chan et al. (1994) identified a somatic gln72-to-leu (Q72L) mutation in the TC21 gene in epithelial ovarian tumor tissue (167000) and demonstrated that the mutation was associated with high transforming activity.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1somaticnot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024