1-114713908-T-C
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1PM1PM2PM5PP3_ModeratePP5
The NM_002524.5(NRAS):c.182A>G(p.Gln61Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q61E) has been classified as Pathogenic.
Frequency
Consequence
NM_002524.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRAS | NM_002524.5 | c.182A>G | p.Gln61Arg | missense_variant | 3/7 | ENST00000369535.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRAS | ENST00000369535.5 | c.182A>G | p.Gln61Arg | missense_variant | 3/7 | 1 | NM_002524.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Sep 03, 2021 | This is a recurrent pathogenic variant that has been reported previously in multiple individuals with kaposiform lymphangiomatosis (KLA), as well as an individual with a generalized lymphatic anomaly (GLA), also known as diffuse lymphangiomatosis (PMID: 30542204, PMID: 31511039, PMID: 29397482). This change is also reported as an oncogenic variant found in multiple tumor types, especially melanoma (COSMIC and cBioPortal Databases). This variant is not present in large population cohorts (Genome Aggregation Database v2.1.1). The p.Gln61Arg variant leads to constitutive activation of the NRAS protein (PMID: 30542204, PMID: 29397482). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2023 | Published functional studies demonstrate increased levels of Nras-GTP (Kong et al., 2016) and constitutive activation of the MAPK pathway (Demin et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 6587382, 14508525, 19880792, 25142146, 22773810, 1654209, 29883661, 18633438, 23392294, 24006476, 20526288, 24077912, 27109513, 31228933, 23855428, 22237106, 17910045) - |
Non-small cell lung carcinoma Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 12, 2011 | - - |
Large congenital melanocytic nevus Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Oct 14, 2023 | The NRAS c.182A>G (p.Gln61Arg) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with melanocytic nevus (Kinsler VA et al., PMID: 23392294; Abdulmajid L et al., PMID: 34255877; Francis JH et al., PMID: 29332123; Colebatch AJ et al., PMID: 30772300; Tschandl P et al., PMID: 23861977; Dessars B et al., PMID: 18633438). This variant has been reported in the ClinVar database as a pathogenic variant by multiple submitters (ClinVar ID: 13900) and in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV54736340). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. The same amino acid change (p.Gln61Arg), resulting from a different nucleotide change, c.182_183delinsGG, has been reported in melanoma and is considered pathogenic (Ball NJ et al., PMID: 8120410; ClinVar ID: 375873). The NRAS c.182A>G (p.Gln61Arg) variant resides within a GTP-binding site of NRAS that is defined as a critical function domain (Scheffzek K et al., PMID: 9219684). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on NRAS function. In support of this prediction, functional studies show that this variant impairs the GTPase activity and activates Ras/Raf/MEK/MAPK pathway, leading to cellular transformation (Ross AL et al., PMID: 21754924; Ruan Y et al., PMID: 25395461). The NRAS gene is defined by the ClinGen's RASopathy expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Gelb BD et al., PMID: 29493581). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the NRAS c.182A>G (p.Gln61Arg) variant is classified as pathogenic. - |
Glioblastoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Adrenal cortex carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Thyroid cancer, nonmedullary, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 2014 | - - |
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Papillary renal cell carcinoma type 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Ovarian serous cystadenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
B-cell chronic lymphocytic leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Multiple myeloma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant neoplasm of body of uterus Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Linear nevus sebaceous syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 2014 | - - |
Nasopharyngeal neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Epidermal nevus Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 2014 | - - |
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of brain Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Melanoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Mar 10, 2016 | - - |
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neurocutaneous melanocytosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 2014 | - - |
Neoplasm of the large intestine Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Noonan syndrome 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at