Total submissions: 39
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000272938 | SCV000329383 | pathogenic | not provided | 2022-12-22 | criteria provided, single submitter | clinical testing | Reported as a somatic variant in affected tissue from individuals with sebaceous nevi; the variant was not detected in blood or unaffected skin tissue of these individuals (Groesser et al., 2012; Levinsohn et al., 2013; Wang et al., 2015); Observed as a presumably somatic variant associated with malignancies, including various types of leukemia (Paulsson et al., 2008; Koorstra et al., 2008; Tyner et al., 2009; Zhang et al., 2011); Published functional studies demonstrate this variant affects GTP binding activity of the KRAS protein (Chen et al., 2013), and causes an increase in AKT phosphorylation (Petrova et al., 2016); Missense variants in this gene are often 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: 18813118, 23096712, 23437064, 24803665, 15093544, 19847165, 22264792, 21451123, 21502497, 18308936, 11323676, 26521233, 20805368, 19075190, 21680795, 30394973, 30936194, 30355600, 31836588, 29298116, 32246016, 30443000, 31891627, 33244099, 22683711, 27362559, 17875937, 29493581, 17910045) |
Invitae | RCV000548006 | SCV000659085 | pathogenic | RASopathy | 2017-06-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with aspartic acid at codon 12 of the KRAS protein (p.Gly12Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs121913529, ExAC 0.01%). This variant has been reported in the literature as a somatic event (present in tissue from a lesion but not in non-lesional tissue or peripheral blood) in individuals with nevus sebaceous syndrome (PMID: 23255105, 22683711, 23096712, 26521233). It was also observed in a child with epidermal nevus, polycystic kidneys, rhabdomyosarcoma and growth retardation (PMID: 20805368). In one family this variant was found in an infant with severe Schimmelpenning syndrome, whereas the monozygotic twin brother was unaffected showing that this variant in the affected individual was due to a postzygotic somatic event (PMID: 22683711, 23255105). ClinVar contains an entry for this variant (Variation ID: 12582). KRAS p.Gly12Asp is a frequently occurring somatic variant in several different types of cancers, including lung, ovarian, endometrial and pancreatic (PMID: 26861459, 1875403, 24629489, 23174937). Experimental studies using mouse knock-in models have shown that this missense change results in the activation of KRAS and increase in proliferation of mouse embryonic cells. In addition, pancreatic tissue from mice expressing this variant show de-differentiation and activation of signaling factors that initiate pancreatic cancer (PMID: 15093544, 25623042). For these reasons, this variant has been classified as Pathogenic. |
Equipe Genetique des Anomalies du Developpement, |
RCV000029215 | SCV001736991 | pathogenic | Linear nevus sebaceous syndrome | criteria provided, single submitter | clinical testing | ||
3billion | RCV000029215 | SCV002318898 | pathogenic | Linear nevus sebaceous syndrome | 2022-03-22 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012582). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012583,VCV000012584, PMID:17704260). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.875>=0.6, 3CNET: 0.995>=0.75). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV000272938 | SCV002525678 | pathogenic | not provided | 2021-08-13 | criteria provided, single submitter | clinical testing | This is a recurrent pathogenic variant that has previously been reported in several individuals with sporadic brain arteriovenous malformations (PMID: 29298116, 30902772, 30544177). The c.35G>A variant substitutes the glycine at codon 12 with aspartic acid. Experimental studies suggest that codon 12 substitutions lead to hyperactivation of the KRAS protein (PMID: 29298116). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000548006 | SCV002601600 | pathogenic | RASopathy | 2022-10-05 | criteria provided, single submitter | clinical testing | Variant summary: KRAS c.35G>A (p.Gly12Asp) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249328 control chromosomes (gnomAD). c.35G>A is a well classified pathogenic somatic mutation (ClinVar ID 2582). c.35G>A has been reported with varying levels of somatic mosaicism in individuals affected with anomalous pancreaticobiliary ductal union, epidermal nevus and Keratinocytic epidermal nevi and Schimmelpenning syndrome characterized by nevus sebaceous and extracutaneous abnormalities (Examples: Shimotake_2003, Bourdeaut_2010 and Hafner_2012, Groesser_2012). Experimental evidence have demonstrated that KRAS G12D is embryonically lethal in the mouse model and conditional expression in mouse embryonic fibroblasts causes enhanced proliferation and partial transformation consistent with a gain of function mechanism of disease (example: Tuveson_2004). A different variant affecting the same residue G12S is associated with Cardio-facio-cutaneous syndrome in HGMD (Nava_2007). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Ce |
RCV000272938 | SCV002821689 | pathogenic | not provided | 2022-12-01 | criteria provided, single submitter | clinical testing | |
Clinical Genomics Laboratory, |
RCV000585796 | SCV004176950 | pathogenic | Cerebral arteriovenous malformation | 2023-11-03 | criteria provided, single submitter | clinical testing | The KRAS c.35G>A (p.Gly12Asp) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with vascular malformations including numerous individuals with brain arteriovenous malformations (Nikolaev SI et al., PMID: 29298116; Lihua J et al., PMID: 29381910; Al-Olabi et al., PMID: 29461977; Goss JA et al., PMID: 31486960; Schmidt FV et al., PMID: 34114335; Mitchell BJ et al., PMID: 30394973). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic variant in both a somatic and germline state by multiple submitters (ClinVar ID: 12582) and in numerous cancer cases as a somatic variant in the cancer database COSMIC (COMIC ID: COSV55497369). This variant is only observed on 2/152,128 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. The KRAS c.35G>A (p.Gly12Asp) variant resides within the P-loop region of KRAS that is defined as a critical functional domain (Gelb BD et al., PMID: 29493581). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KRAS function. In support of this prediction, functional studies show that this variant activates mitogen-activated protein kinase kinase 1 signaling pathway, leading to the formation of vascular malformation (Cistea IC et al., PMID: 23059812; Fish JE et al., PMID: 32552404; Janardhan HP et al., PMID: 32405640). The KRAS gene is defined by the ClinGen's RASopathies 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 KRAS c.35G>A (p.Gly12Asp) variant is classified as pathogenic. |
Ambry Genetics | RCV004018620 | SCV005023563 | likely pathogenic | Cardiovascular phenotype | 2022-08-22 | criteria provided, single submitter | clinical testing | reported for somatic cases only, for germline findings, please reassess |
New York Genome Center | RCV004554600 | SCV005044128 | pathogenic | Congenital Pulmonary Airway Malformations | 2022-07-19 | criteria provided, single submitter | clinical testing | The c.35G>A variant in KRAS is an established pathogenic variant almost always exclusively found in tissue analysis of individuals with somatic cancers or tissue-limited phenotypes, and it has been deposited in ClinVar [ClinVar ID: 12582] as Pathogenic. The c.35G>A variant is observed in 5 alleles with 0 homozygote in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), which might be due to clonal hematopoesis of indeterminate potential or emerging/existing hematologic malignancies in variant carrying individuals in those databases. The c.35G>A variant in KRAS is located in exon 2 of this 5-exon gene, and is predicted to replace an evolutionarily conserved glycine amino acid with aspartate at position 12 (p.Gly12Asp) in the encoded protein. The p.Gly12Asp variant has been demonstrated to confer oncogenic potential via inhibiting the GTPase activity that result in continuous GTP-bound, active state [PMID: 11323676, 27096871]. Although another variant at codon 12 (p.Gly12Ser) has been reported in the germline of individuals with RASopathy phenotypes [PMID: 17704260, 26242988], p.Gly12Asp variant has not been reported constitutionally. The p.Gly12Asp variant has recently been identified in CPAM sections of individuals at less than 35% variant allele fraction (VAF) while the nearby unaffected lung tissue sections were found to be not carrying the p.Gly12Asp variant [PMID: 35794233]. The c.35G>A variant has been found at 28% VAF (13/47 reads) in this fetal sample, which might reflect the tissue-limited mosaicism of respiratory tract cells present in the amniotic fluid. Based on available evidence this de novo mosaic c.35G>A p.Gly12Asp variant identified in KRAS is classified as Pathogenic. |
OMIM | RCV000013411 | SCV000033658 | pathogenic | Carcinoma of pancreas | 2012-06-10 | no assertion criteria provided | literature only | |
OMIM | RCV002508117 | SCV000033659 | pathogenic | Gastric cancer | 2012-06-10 | no assertion criteria provided | literature only | |
OMIM | RCV000022799 | SCV000044088 | pathogenic | Epidermal nevus | 2012-06-10 | no assertion criteria provided | literature only | |
OMIM | RCV000029214 | SCV000051860 | pathogenic | Nevus sebaceous | 2012-06-10 | no assertion criteria provided | literature only | |
OMIM | RCV000029215 | SCV000051861 | pathogenic | Linear nevus sebaceous syndrome | 2012-06-10 | no assertion criteria provided | literature only | |
OMIM | RCV000144969 | SCV000191996 | pathogenic | Juvenile myelomonocytic leukemia | 2012-06-10 | no assertion criteria provided | literature only | |
OMIM | RCV000144970 | SCV000191997 | pathogenic | Autoimmune lymphoproliferative syndrome type 4 | 2012-06-10 | no assertion criteria provided | literature only | |
Laboratory for Molecular Medicine, |
RCV000144969 | SCV000198478 | pathogenic | Juvenile myelomonocytic leukemia | 2014-08-28 | no assertion criteria provided | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000150896 | SCV000198479 | pathogenic | Non-small cell lung carcinoma | 2014-08-28 | no assertion criteria provided | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000150897 | SCV000198480 | pathogenic | Neoplasm of ovary | 2014-08-28 | no assertion criteria provided | clinical testing | Somatic KRAS variants have been identified in up to 15% of cases of ovarian carcinoma, and Gly12Asp accounts for 40% of the identified KRAS variants (COSMIC 2010; Auner 2009). |
Database of Curated Mutations |
RCV000426369 | SCV000504481 | pathogenic | Neoplasm of the large intestine | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433573 | SCV000504482 | likely pathogenic | Acute myeloid leukemia | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443973 | SCV000504483 | pathogenic | Thyroid tumor | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425250 | SCV000504484 | likely pathogenic | Lung carcinoma | 2016-03-10 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000150897 | SCV000504485 | pathogenic | Neoplasm of ovary | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000150896 | SCV000504486 | pathogenic | Non-small cell lung carcinoma | 2016-03-10 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000013411 | SCV000504487 | not provided | Carcinoma of pancreas | 2016-03-10 | no assertion provided | literature only | |
Yale Center for Mendelian Genomics, |
RCV000029214 | SCV000611562 | pathogenic | Nevus sebaceous | 2012-10-25 | no assertion criteria provided | literature only | |
OMIM | RCV000585796 | SCV000693723 | pathogenic | Cerebral arteriovenous malformation | 2018-03-06 | no assertion criteria provided | literature only | |
Yale Center for Mendelian Genomics, |
RCV000662266 | SCV000784594 | likely pathogenic | Vascular Tumors Including Pyogenic Granuloma | 2015-02-19 | no assertion criteria provided | literature only | |
Thoracic Oncology Service, |
RCV000150896 | SCV000882686 | pathogenic | Non-small cell lung carcinoma | no assertion criteria provided | research | ||
Laboratory for Clinical Genomics and Advanced Technology, |
RCV000013411 | SCV000882700 | pathogenic | Carcinoma of pancreas | 2019-02-07 | no assertion criteria provided | research | Variant causes impairment of the intrinsic GTPase activity of KRAS and subsequent activation of downstream signaling pathways that drive cancer growth. |
Arin Greene Laboratory, |
RCV000585796 | SCV000992585 | pathogenic | Cerebral arteriovenous malformation | no assertion criteria provided | research | ||
University Health Network, |
RCV000856666 | SCV000999192 | pathogenic | Primary low grade serous adenocarcinoma of ovary | 2019-11-04 | no assertion criteria provided | research | |
Department of Pathology and Laboratory Medicine, |
RCV000272938 | SCV001550138 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Hematopathology, |
RCV000433573 | SCV001571657 | pathogenic | Acute myeloid leukemia | 2018-03-30 | no assertion criteria provided | clinical testing | |
Arin Greene Laboratory, |
RCV001799604 | SCV001739511 | pathogenic | Capillary malformation-arteriovenous malformation 1 | 2021-05-01 | no assertion criteria provided | research | |
Gene |
RCV001839445 | SCV002099547 | not provided | Encephalocraniocutaneous lipomatosis | no assertion provided | literature only | ||
Martignetti Lab, |
RCV003327361 | SCV004035006 | association | Endometrial hyperplasia without atypia; Atypical endometrial hyperplasia | no assertion criteria provided | research |