ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2671T>G (p.Ser891Ala) (rs75234356)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000193761 SCV000248717 pathogenic Multiple endocrine neoplasia IIA 2014-10-20 criteria provided, single submitter clinical testing
Invitae RCV000227193 SCV000290551 pathogenic Multiple endocrine neoplasia, type 2 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 891 of the RET protein (p.Ser891Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals and families affected with medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and parathyroid hyperplasia (PMID: 20554711, 9398735, 24845513, 24449023, 23295303). According to the management guidelines of the American Thyroid Association (ATA), this variant is categorized as a moderate risk variant for MTC with ~10% incidence of PHEO or hyperparathyroidism (HPTH) (PMID: 25810047, 19469690, 11739416). ClinVar contains an entry for this variant (Variation ID: 13951). Experimental studies have shown that this missense change increases the phosphorylation levels of downstream effectors such as Akt and STAT3, and has a moderate transforming activity in vitro (PMID: 10445857, 17209045, 26356818). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000394478 SCV000329492 pathogenic not provided 2017-08-17 criteria provided, single submitter clinical testing TThe S891A variant in the RET gene has previously been reported in association with familial medullary thyroid cancer (FMTC) and multiple endocrine neoplasia type 2 (MEN2) (for examples, see Hofstra et al., 1997; Elisei et al., 2007; Qi et al., 2014; Sromek et al., 2017). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S891A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, we consider S891A to be pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000227193 SCV000711449 pathogenic Multiple endocrine neoplasia, type 2 2017-06-20 criteria provided, single submitter clinical testing The p.Ser891Ala variant in RET is an established pathogenic variant for multiple endocrine neoplasia type 2 (MEN2). It accounts for up to 5% of all patients re ported with RET mutations and has been shown to segregate with disease in at lea st 15 affected individuals across several families. This variant has been report ed in ClinVar (Variation ID 13951) and is classified by the American Thyroid Ass ociation as imparting a moderate risk to developing aggressive medullary thyroid carcinoma (Wells 2015). Most individuals with this variant have familial medull ary thyroid carcinoma (Hofstra 1997, Dang 1999, Yip 2003, Jimenez 2004, Elisei 2 007, Romei 2010, Blom 2012, Qi 2014), although at least 8 individuals were diagn osed with MEN2A (Asari 2006, Machens 2008, Schulte 2010, Hibi 2014). This varian t was absent from large population studies. In vitro functional studies provide some evidence that the p.Ser891Ala variant may impact protein function (Iwashita 1999, Plaza Menacho 2005, Colombo 2015). In summary, this variant meets criteri a to be classified as pathogenic for MEN2 in an autosomal dominant manner based upon multiple case reports, functional evidence, and absence from controls. ACMG /AMP criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting (Richards 2015).
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000014978 SCV000782259 pathogenic Multiple endocrine neoplasia, type 2a 2016-11-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000394478 SCV000842757 pathogenic not provided 2018-07-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999915 SCV000886054 pathogenic not specified 2019-03-15 criteria provided, single submitter clinical testing The RET c.2671T>G; p.Ser891Ala variant (rs75234356) has been described in the medical literature in individuals and families with medullary thyroid carcinoma and pheochromocytoma (Shulte 2010), and is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13951). Additionally, according to the American Thyroid Association, this variant is classified as a moderate risk variant for medullary thyroid carcinoma with a low incidence of pheochromocytoma or hyperparathyroidism (Wells 2015). This variant is only observed in 3 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 891 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. The variant has also been shown to have some transforming activity (Iwashita 1999). Based on available information, this variant is considered to be pathogenic. REFERENCES Iwashita T et al. Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene. 1999 Jul 1;18(26):3919-22. Schulte KM et al. The clinical spectrum of multiple endocrine neoplasia type 2a caused by the rare intracellular RET mutation S891A. J Clin Endocrinol Metab. 2010 Sep;95(9):E92-7. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610.
Ambry Genetics RCV001016276 SCV001177214 pathogenic Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Strong segregation with disease (lod >3 = >10 meioses)
OMIM RCV000014978 SCV000035234 pathogenic Multiple endocrine neoplasia, type 2a 2004-08-01 no assertion criteria provided literature only
OMIM RCV000014979 SCV000035235 pathogenic Familial medullary thyroid carcinoma 2004-08-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000227193 SCV000042541 pathogenic Multiple endocrine neoplasia, type 2 2019-05-01 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 13 yr. Reports of Pheo, parathyroid hyperplasia, and corneal nerve thickening (PMID 20554711, 15292360, 17178962, and 12686527). In vitro studies: RET activation (PMID 10445857 and 15753368). Additional references: PMID 18062802, 30927507, and 17895320. Has been found with another RET change, see c.[1573C>T ];[ 2671T>G].
Database of Curated Mutations (DoCM) RCV000431535 SCV000510537 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441854 SCV000510538 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425892 SCV000510539 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000014978 SCV000510540 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445273 SCV000510541 likely pathogenic Medullary thyroid carcinoma 2016-05-13 no assertion criteria provided literature only

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