chr10-43114494-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_020975.6(RET):c.1894G>A(p.Glu632Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,607,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E632D) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1894G>A | p.Glu632Lys | missense_variant | 11/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1894G>A | p.Glu632Lys | missense_variant | 11/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 151912Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000971 AC: 24AN: 247226Hom.: 0 AF XY: 0.000112 AC XY: 15AN XY: 134056
GnomAD4 exome AF: 0.0000433 AC: 63AN: 1455192Hom.: 0 Cov.: 33 AF XY: 0.0000497 AC XY: 36AN XY: 724220
GnomAD4 genome AF: 0.0000658 AC: 10AN: 152030Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 15, 2019 | The RET c.1894G>A; p.Glu632Lys variant has been described in individuals affected with medullary thyroid cancer (MTC), Hirschsprung's disease, or pheochromocytoma (Carter 2012, Frank-Raue 2007, Han 2006, Romei 2015). It is reported as a variant of uncertain significance multiple times in ClinVar (Variation ID: 24920), and is observed in the general population at an overall frequency of 0.01% (24/247226 alleles) in the Genome Aggregation Database. The glutamic acid at codon 632 is moderately conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is tolerated. Due to limited information, the clinical significance of this variant cannot be determined with certainty. REFERENCES Carter TC et al. Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. J Hum Genet. 2012 Aug;57(8):485-93. Frank-Raue K et al. Change in the spectrum of RET mutations diagnosed between 1994 and 2006. Clin Lab. 2007;53(5-6):273-82. Han ZY et al. Mutation screening of RET proto-oncogene in Chinese sporadic patients with pheochromocytoma. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006 Jun;23(3):320-2. Romei C et al. Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? Clin Endocrinol (Oxf). 2015 Jun;82(6):892-9. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17605401, 21479187, 16767674, 25440022, 34169762, 34570441, 31510104, 22648184, 30217742, 31159747, 14633923) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | RET: PM1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 12, 2021 | The p.Glu632Lys variant in RET has been reported in 2 individuals with Hirschsprung's disease, 1 individual with medullary thyroid carcinoma, and 1 individual tested for a hereditary cancer panel (Carter 2011 PMID: 22648184, Romei 2015 PMID: 25440022, Tang 2018 PMID: 30217742, Tsaousis 2019 PMID: 31159747). It has also been identified in 0.05% (14/30612) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 05, 2021 | - - |
Multiple endocrine neoplasia type 2A Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS) | Jun 10, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 14, 2015 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Multiple endocrine neoplasia type 2B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 14, 2015 | - - |
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 632 of the RET protein (p.Glu632Lys). This variant is present in population databases (rs377767407, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 17605401, 22648184, 25440022, 30217742, 31510104). ClinVar contains an entry for this variant (Variation ID: 24920). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at