10-43114501-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_020975.6(RET):c.1901G>A(p.Cys634Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,706 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C634F) 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.1901G>A | p.Cys634Tyr | missense_variant | Exon 11 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247574Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134198
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1455706Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2AN XY: 724436
GnomAD4 genome
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia type 2A Pathogenic:8
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The observed missense c.1901G>A (p.Cys634Tyr) variant in RET gene has been reported in multiple individuals affected with RET-related disorders (Chiefari et al., 1998; Sánchez et al., 1999; Jackson et al., 2005; Valente et al., 2013; Valdés et al., 2015). It has also been observed to segregate with disease in related individuals (Valente et al., 2013). Amino acid position 634 is a well described mutation hot spot associated with Multiple endocrine neoplasia type 2A (MEN2A). Functional characterization of the p.Cys634Tyr variant and other missense variants at the same amino acid position (p.Cys634Arg, p.Cys634Trp) indicated increased auto-phosphorylation and activation of downstream targets, resulting in enhanced malignant transformation of cells (Cosci et al., 2011, Santoro et al., 1995). This variant is present with allele frequency of 0.0004% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Cys634Tyr in RET is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 634 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: RET c.1901G>A (p.Cys634Tyr) results in a non-conservative amino acid change located in the extracellular domain of the encoded protein sequence. Five 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 247574 control chromosomes. c.1901G>A has been well reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A (example Chiefari_1998, Frank-Raue_2006). These data indicate that the variant is strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a gain of function mechanism due to activation of the RET proto-oncogene (example Santoro_1995). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192, 21834681]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26732158, 17188172, 34439168, 20801952, 33827484, 25810047]. -
not provided Pathogenic:7
Published functional studies demonstrate a damaging effect: high transforming ability, constitutive kinase activation (Santoro 1995, Ito 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(Cys380Tyr); This variant is associated with the following publications: (PMID: 12711285, 8797874, 9146685, 23723040, 19062722, 27558615, 25515555, 26254625, 29133048, 29656518, 23330657, 7835899, 21765987, 7824936, 8099202, 15858153, 8626834, 21054478, 16314641, 17895320, 24716929, 12000816, 7874109, 20080836, 26732158, 28099363, 26758973, 26572832, 26876062, 27539324, 23868299, 11987030, 30139385, 29197744, 7881414, 9230192, 28469506, 30113649, 21655256, 18063059, 12686527, 9950371, 7860065, 16099853, 11524247, 19240193, 7914213, 7491519, 12604374, 9820617, 9699127, 31062739, 30122763, 16158949, 20516206, 29625052, 31510104, 32989896, 8909322, 18096130, 9497883, 8984233, 35627249, 28152038, 30763276, 9706252, 25545346, 33340421, 33219105, 35418818, 14633923) -
The RET c.1901G>A;p.Cys634Tyr variant (rs75996173) is reported in the literature in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (American Thyroid Association Guidelines Task Force 2009, Punales 2003, Wells 2015). This variant is found on a single chromosome in the Genome Aggregation Database (1/247574 alleles), indicating it is not a common polymorphism. The cysteine at codon 634 is highly conserved, and other amino acid substitutions at this codon (Arg, Gly, Phe, Ser, Trp) are considered causative for MEN2A (Wells 2015). Functional characterization of the p.Cys364Tyr variant and other missense variants at the same codon (p.Cys634Arg, p.Cys634Trp) indicates increased auto-phosphorylation and activation of downstream targets (Santoro 1995), resulting in enhanced malignant transformation of cells (Cosci 2011, Santoro 1995). Based on available information, the p.Cys634Tyr variant is considered to be pathogenic. References: American Thyroid Association Guidelines Task Force et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun;19(6):565-612. PMID: 19469690. Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011 Sep 20;18(5):603-12. PMID: 21810974. Punales MK et al. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003 Jun;88(6):2644-9. PMID: 12788868. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381-3. PMID: 7824936. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. PMID: 25810047. -
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The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with MEN2A. The American Thyroid Association has placed this variant into the ATA-H category, formerly known as level C, for having a high risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 7824936, 9230192) -
The RET c.1901G>A (p.Cys634Tyr) variant has been reported in the published literature in multiple individuals with MEN2A and/or FMTC (PMID: 7835899 (1994), 9950371 (1999), 12000816 (2002), 21765987 (2011), 25810047 (2015), 26732158 (2016), 28099363 (2017), 33167350 (2020)). A functional study found the variant has a damaging effect on RET function (PMID: 7824936 (2015)). The frequency of this variant in the general population, 0.000004 (1/247574 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
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Multiple endocrine neoplasia type 2B Pathogenic:2
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The family RET mutation (C634Y) was detected in this blood specimen. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909) with 22 submissions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 7824936). This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8099202, 12000816, 21765987). Therefore, this variant has been classified as Pathogenic. -
Pheochromocytoma Pathogenic:2
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Hirschsprung disease, susceptibility to, 1 Pathogenic:2
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Multiple endocrine neoplasia, type 2 Pathogenic:1
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909). 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. Experimental studies have shown that this missense change affects RET function (PMID: 7824936). This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8099202, 12000816, 21765987). 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. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C634Y pathogenic mutation (also known as c.1901G>A) is located in coding exon 11 of the RET gene. This alteration results from a G to A substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C634Y mutation has been reported in several unrelated families diagnosed with MEN2A and/or familial medullary thyroid carcinoma (FMTC) (Mulligan et al. Nature. 1993;363:458-460; Marsh DJ et al. Genomics. 1994;23(2):477-479; Hedayati et al. J Thyroid Res. 2011;2011:264248; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). Amino acid position 634 is a well described mutation hot spot associated with MEN2A/FMTC. Studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Neumann HP et al. N. Engl. J. Med. 2002;346:1459-66, Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003;138:409-16). Revised American Thyroid Association Guidelines categorize the p.C634Y alteration as high risk (ATA-H) and recommend surveillance and prophylactic surgery in early childhood (Wells SA et al. Thyroid 2015 Jun;25(6):567-610). Of note, this alteration has been referred to as p.C380Y (c.1832G>A) and p.C634Y (c.2096G>A) in the published literature. Based on the available evidence, p.C634Y is classified as a pathogenic mutation. -
RET-related disorder Pathogenic:1
The RET c.1901G>A variant is predicted to result in the amino acid substitution p.Cys634Tyr. This variant has been reported in multiple individuals with MEN2A, medullary thyroid cancer, and pheochromocytoma (Mulligan et al. 1993. PubMed ID: 8099202; Sanchez et al. 1999. PubMed ID: 9950371; Toledo et al. 2010. PubMed ID: 20080836). Functional studies have shown this variant and other amino acid changes at this position result in increased auto-phosphorylation and activation of downstream targets which enhances malignant transformation of cells (Santoro M et al. 1995. PubMed ID: 7824936; Cosci B et al. 2011. PubMed ID: 21810974). This variant is present in one individual in the gnomAD database. This variant is classified as pathogenic in ClinVar with multiple submitters in agreement (https://www.ncbi.nlm.nih.gov/clinvar/variation/13909/). We interpret this variant to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at