10-43114500-T-A
Variant summary
Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_020975.6(RET):c.1900T>A(p.Cys634Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 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. C634L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 26 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1900T>A | p.Cys634Ser | missense_variant | 11/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1900T>A | p.Cys634Ser | missense_variant | 11/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple endocrine neoplasia type 2 (MEN 2) and medullary thyroid carcinoma (MTC) (PMID: 9467562, 15277225, 21765987, 25143909, 25440022, 28099363). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38605). 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: 15277225, 29312610). 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: 7824936, 8103403, 8570194, 15472167, 21810974, 23210566, 23617071, 27698838). 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
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2023 | The p.C634S pathogenic mutation (also known as c.1900T>A), located in coding exon 11 of the RET gene, results from a T to A substitution at nucleotide position 1900. The cysteine at codon 634 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in numerous families with multiple endocrine neoplasia type 2A (MEN2A) or familial medullary thyroid cancer (FMTC) and has been shown to segregate with disease in many of these families (Mulligan LM et al. Nat. Genet. 1994 Jan;6:70-4; Hedayati M et al. J Thyroid Res. 2011 Jun;2011:264248; Mahesh DM et al. Indian J Endocrinol Metab. 2014 Jul;18:516-20; Moore SW et al. J. Pediatr. Surg. 2007 Feb;42:326-32; Zhou Y et al. Clin. Endocrinol. (Oxf). 2007 Oct;67:570-6; Ambry internal data). This alteration has been shown by functional studies to lead to constitutive activation of RET tyrosine kinase and constitutive phosphorylation of MAPK (Melillo RM et al. Am. J. Pathol. 2004 Aug;165:511-21). This mutation occurs at a known hotspot and studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003; 138:409-16). Of note, the American Thyroid Association recommends that individuals with mutations in codon 634 begin surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid 2009 Jun;19(6):565-612). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at