rs77316810
Variant summary
Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_StrongPM2PM5PP3_StrongPP5_Very_Strong
The NM_020975.6(RET):c.1858T>A(p.Cys620Ser) variant causes a missense change. 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 Likely pathogenic (★★). 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. C620F) has been classified as Pathogenic.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 24 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1858T>A | p.Cys620Ser | missense_variant | 10/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1858T>A | p.Cys620Ser | missense_variant | 10/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 31, 2023 | This missense variant replaces cysteine with serine at codon 620 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with MEN2/familial medullary thyroid carcinoma (PMID: 7849720, 11238493) or suspected MEN2A case (PMID: 14718397). Another variant with the same protein change is known to be disease-causing (c.1859G>C, p.Cys620Ser; ClinVar Variation ID: 13943). Mutations at this codon have been categorized by the American Thyroid Association as having moderate risk for MTC and is associated with a pheochromocytoma incidence rate of 13%-24% (PMID: 25810047). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 07, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys620 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7874109, 8909322, 16705552, 20979234, 21765987). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RET function (PMID: 9230192). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 38602). This missense change has been observed in individuals with multiple endocrine neoplasia type 2 and/or Hirschsprung disease (PMID: 10777380, 11471675, 14517954). It has also been observed to segregate with disease in related individuals. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 620 of the RET protein (p.Cys620Ser). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This missense variant replaces cysteine with serine at codon 620 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with MEN2/familial medullary thyroid carcinoma (PMID: 7849720, 11238493) or suspected MEN2A case (PMID: 14718397). Another variant with the same protein change is known to be disease-causing (c.1859G>C, p.Cys620Ser; ClinVar Variation ID: 13943). Mutations at this codon have been categorized by the American Thyroid Association as having moderate risk for MTC and is associated with a pheochromocytoma incidence rate of 13%-24% (PMID: 25810047). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 06, 2018 | The p.C620S pathogenic mutation (also known as c.1858T>A), located in coding exon 10 of the RET gene, results from a T to A substitution at nucleotide position 1858. The cysteine at codon 620 is replaced by serine, an amino acid with dissimilar properties. This pathogenic mutation has been reported in the germline of a 44 year old Italian individual diagnosed with a unilateral pheochromocytoma and a family history consistent with MEN2 (Iacobone M et al. Surgery. 2011 Dec;150:1194-201). In addition, this mutation is located in codon 620, which encodes part of the extracellular cysteine rich domain and is a well-described mutation hotspot site. Mutations at this codon have been categorized by the American Thyroid Association as having moderate risk for MTC and is associated with a pheochromocytoma incidence rate of 13%–24% (Wells SA et al. Thyroid. 2015 Jun;25:567-610). Based on the available evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at