Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS1_Very_StrongPM1PM2_SupportingPM5PP3_StrongPP5_Very_Strong
The NM_020975(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 Genomes 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. C634F) has been classified as Pathogenic.
Verdict is Pathogenic. Variant got 25 ACMG points.
GnomAD3 genomesCov.: 32
Submissions by phenotype
Multiple endocrine neoplasia, type 2
|Pathogenic, criteria provided, single submitter||clinical testing||Invitae||Jul 31, 2019||This sequence change replaces cysteine with serine at codon 634 of the RET protein (p.Cys634Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with medullary thyroid carcinoma (MTC) in several families (PMID: 15277225, 25143909, 21765987). It has also been observed in individuals affected with MTC and multiple endocrine neoplasia type 2 (MEN 2) (PMID: 28099363, 25440022, 9467562). ClinVar contains an entry for this variant (Variation ID: 38605). Experimental studies have shown that this missense change disrupts RET protein function (PMID: 29312610, 15277225). The p.Cys634 amino acid residue in RET has been determined to be clinically significant (PMID: 8103403, 27698838, 22900816, 23617071, 15472167, 21810974, 8570194, 7824936). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -|
Hereditary cancer-predisposing syndrome
|Pathogenic, criteria provided, single submitter||clinical testing||Ambry Genetics||Dec 28, 2016||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). 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). Based on the available evidence, p.C634S is classified as a pathogenic mutation. Of note, the American Thyroid Association recommends that individuals with mutation 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). -|
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