rs79781594
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_020975.6(RET):c.1853G>A(p.Cys618Tyr) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C618R) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1853G>A | p.Cys618Tyr | missense_variant | Exon 10 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Pathogenic:2
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 618 of the RET protein (p.Cys618Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple endocrine neoplasia type 2A and familial medullary thyroid cancer (PMID: 8103403, 20516206, 21765987, 25628771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24901). 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. Experimental studies have shown that this missense change affects RET function (PMID: 7824936, 9174404, 9230192, 9879991). This variant disrupts the p.Cys618 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7915165, 9384613, 9498388, 9839497, 20979234, 22068382; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: RET c.1853G>A (p.Cys618Tyr) results in a non-conservative amino acid change located at a critical residue within the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249080 control chromosomes. c.1853G>A has been widely reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma and subsequently cited by others (example, Donis-Keller_1993, Chiefari_1998, Beldjord_1995, Kimura_1995, Landsvater_1996). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in transforming activity of the RET proto-oncogene and reduced cell surface expression suggesting the potential to develop Hirschsprung's disease in addition to MEN 2A and FMTC (Ito_1997). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
Published functional studies demonstrate a damaging effect: increased transforming activity and homodimer formation (PMID: 9230192); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9879991, 9498388, 20979234, 23660264, 9839497, 8918855, 10490816, 7824936, 9174404, 19469690, 9384613, 7915165, 22068382, 26343386, 9699127, 7608256, 22747440, 8103403, 18063059, 20516206, 21765987, 11230481, 9761126, 31510104, 14633923, 29020875, 30666164, 26582918, 35053433, 37046785, 33827484, 32665702, 25628771, 9230192) -
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Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C618Y pathogenic mutation (also known as c.1853G>A), located in coding exon 10 of the RET gene, results from a G to A substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in multiple individuals diagnosed with medullary thyroid carcinoma (MTC) and/or MEN2A (Frank-Raue K et al. Hum Mutat. 2011 Jan;32(1):51-8; Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4; Quayle FJ et al. Surgery 2007 Dec;142(6):800-5; discussion 805.e1; Zhao JQ et al. Hered Cancer Clin Pract. 2015 Jan;13(1):5). In addition, several other missense alterations that change the cysteine at codon 618 have been reported in the literature as disease-causing mutations (Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). The American Thyroid Association categorizes alterations to the C618 residue, including p.C618Y, in the B-level risk group and has made mutation specific guidelines available (Kloos RT et al. Thyroid 2009 Jun; 19(6):565-612). Based on the supporting 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