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

gnomAD frequency: 0.00001  dbSNP: rs75234356

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000014978	SCV000248717	pathogenic	Multiple endocrine neoplasia, type 2a	2014-10-20	criteria provided, single submitter	clinical testing
Invitae	RCV000227193	SCV000290551	pathogenic	Multiple endocrine neoplasia, type 2	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 891 of the RET protein (p.Ser891Ala). This variant is present in population databases (rs75234356, gnomAD 0.006%). This missense change has been observed in individual(s) with medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and parathyroid hyperplasia. 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: 9398735, 11739416, 19469690, 20554711, 23295303, 24449023, 24845513, 25810047). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13951). 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: 10445857, 17209045, 26356818). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000394478	SCV000329492	pathogenic	not provided	2020-12-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced transforming activity in vitro (Iwashita 1999, Colombo 2015); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10445857, 15753368, 11849247, 31447099, 15184865, 17895320, 23295303, 9398735, 18062802, 24845513, 20554711, 24449023, 15292360, 26356818, 27809725, 28647780, 28609830, 28729773, 17178962, 12686527, 25810047, 19469690, 11739416, 20516206, 10024437, 17209045, 25887804, 29727688, 30927507, 30763276, 31510104, 32179705)
Laboratory for Molecular Medicine, Mass General Brigham 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	2023-01-25	criteria provided, single submitter	clinical testing	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 medullary thyroid cancer and MEN2A. The American Thyroid Association has placed this variant into the ATA-MOD category, which includes the former levels A and B, for having a moderate risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10445857, 15753368, 25887804)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000394478	SCV000886054	pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing	The RET c.2671T>G; p.Ser891Ala variant (rs75234356) is reported in the literature in individuals and families with medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism (Elisei 2019, Hofstra 1997, Qi 2021, Shulte 2010). This variant is also reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13951). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Functional analyses of the variant protein show that it has low transforming activity (Colombo 2015, Iwashita 1999, Plaza Menacho 2005). Additionally, according to the American Thyroid Association, this variant is classified as a moderate risk variant for aggressive medullary thyroid carcinoma with a low incidence of pheochromocytoma or hyperparathyroidism (Wells 2015). Computational analyses predict that this variant is deleterious (REVEL: 0.733). Based on available information, this variant is considered to be pathogenic. References: Colombo C et al. The modifier role of RET-G691S polymorphism in hereditary medullary thyroid carcinoma: functional characterization and expression/penetrance studies. Orphanet J Rare Dis. 2015 Mar 1;10:25. PMID: 25887804. Elisei R et al. Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations. Genes (Basel). 2019 Sep 10;10(9):698. PMID: 31510104. Hofstra RM et al. A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab. 1997 Dec;82(12):4176-8. PMID: 9398735. 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. PMID: 10445857. Plaza Menacho I et al. RET-familial medullary thyroid carcinoma mutants Y791F and S891A activate a Src/JAK/STAT3 pathway, independent of glial cell line-derived neurotrophic factor. Cancer Res. 2005 Mar 1;65(5):1729-37. PMID: 15753368. Qi XP et al. Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China. BMC Cancer. 2021 Apr 7;21(1):369. PMID: 33827484. 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. PMID: 20554711. Wells SA et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. PMID: 25810047.
Ambry Genetics	RCV001016276	SCV001177214	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	clinical testing	The p.S891A pathogenic mutation (also known as c.2671T>G), located in coding exon 15 of the RET gene, results from a T to G substitution at nucleotide position 2671. The serine at codon 891 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in numerous ancestrally diverse individuals diagnosed with medullary thyroid cancer (MTC) or pheochromocytoma, or have a diagnosis of familial medullary thyroid cancer (FMTC) or multiple endocrine neoplasia type 2A (MEN2A) (Hofstra RM et al. J. Clin. Endocrinol. Metab. 1997 Dec;82:4176-8; Dang GT et al. Mol. Cell. Probes. 1999 Feb;13:77-9; Jimenez C et al. J. Clin. Endocrinol. Metab. 2004 Aug;89:4142-5; Plaza Menacho I et al. Cancer Res. 2005 Mar;65:1729-37; Hibi Y et al. Surg. Today. 2014 Nov;44:2195-200; Sromek M et al. Endocr. Pathol. 2017 Sep;28:198-206; Maciel RMB et al. Endocr Connect. 2019 03;8:289-298; Qi XP et al. BMC Cancer. 2021 Apr;21:369). One study summarizing data on seventy-four p.S891A mutation carriers found that while the majority had a FMTC phenotype, others had a MEN2A phenotype with early-onset MTC, invasive pheochromocytomas, and/or corneal nerve thickening (Schulte KM et al. J Clin Endocrinol Metab. 2010 Sep;95:E92-7). One study reported 2 of 12 families with p.S891A also had relatives with Hirschsprung disease in addition to MTC (Elisei R et al. Genes (Basel). 2019 09;10:). This alteration as also identified in a patient diagnosed with MTC at 32 and then small cell osteosarcoma at age 34; his mother also was diagnosed with MTC at age 66. Analysis of the osteosarcoma identified this alteration in the hemizygous state as there was also copy number loss of part of chromosome 10 (Kovac M et al. J Med Genet. 2021 01;58:20-24). Experimental studies have demonstrated that this alteration results in a moderate transforming activity in in vitro assays and increases phosphorylation levels of downstream effectors (Iwashita T et al. Oncogene. 1999 Jul;18:3919-22; Plaza-Menacho I et al. J Biol Chem. 2007 Mar;282:6415-24; Qi XP et al. Oncotarget. 2015 Oct;6:33993-4003). The American Thyroid Association has designated this mutation as conferring moderate risk for MTC (formerly category A) (Wells SA et al. Thyroid. 2015 Jun; 25(6):567-610). Based on the supporting evidence, this variant is expected to be causative of MEN2A/ FMTC; however, its clinical significance for Hirschsprung disease is unclear.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000394478	SCV001449923	pathogenic	not provided	2018-05-16	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000014979	SCV001499815	pathogenic	Familial medullary thyroid carcinoma	2020-04-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000394478	SCV002020788	pathogenic	not provided	2019-05-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804732	SCV002051352	pathogenic	MEN2 phenotype: Unclassified	2021-12-23	criteria provided, single submitter	clinical testing	Variant summary: RET c.2671T>G (p.Ser891Ala) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250656 control chromosomes. c.2671T>G has been widely reported in the literature in multiple individuals undergoing evaluation for medullary carcinoma of the thyroid (MTC), pheochromocytoma (PHEO) and primary hyperparathyroidism (example, Hofstra_1997, Schulte_2010). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (example, Iwashita_1999, Plaza-Menacho_2007). The most pronounced variant effect results in increased transforming activity and constitutive kinase activity as monitored by RET phosphorylation and downstream phosphorylation of ERK 1/2. These findings are consistent with the established gain of function mechanism of disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000394478	SCV002522520	pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	PP1_strong, PP5, PM2, PS3_supporting, PS4_moderate
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000394478	SCV002774398	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000012 (3/250656 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in many individuals with multiple endocrine neoplasia type 2A, familial medullary thyroid cancer, or pheochromocytoma (PMIDs: 23295303 (2012), 24449023 (2014), 24845513 (2014), 25887804 (2015), and 26356818 (2015)). Functional studies indicate that this variant impacts protein function (PMIDs: 16469774 (2006), 26356818 (2015), 15753368 (2005)). Therefore, the variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490368	SCV002800535	pathogenic	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a	2021-08-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000425892	SCV004015164	pathogenic	Multiple endocrine neoplasia, type 2b	2023-07-07	criteria provided, single submitter	clinical testing	The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. This variant is not in gnomAD. 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) with 18 submissions, all of which describe it as of uncertain significance. UniProt Variants classifies this variant as Pathogenic, citing 3 articles (15292360, 10024437 and 9398735). 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). In-silico predictions show pathogenic computational verdict based on 11 pathogenic predictions from PolyPhen, BayesDel_addAF, DANN, DEOGEN2, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 1 benign prediction from MutationAssessor (1 uncertain prediction from EIGEN). Therefore, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387503	SCV004099226	pathogenic	Medullary thyroid carcinoma; Multiple endocrine neoplasia II	2023-07-20	criteria provided, single submitter	clinical testing	PS4, PS3
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
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