rs75234356

chr10-43120144-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_020975.6(RET):c.2671T>G(p.Ser891Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,876 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S891S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 5.14

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788
• PP5: Variant 10-43120144-T-G is Pathogenic according to our data. Variant chr10-43120144-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 13951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43120144-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.2671T>G	p.Ser891Ala	missense_variant	15/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.2671T>G	p.Ser891Ala	missense_variant	15/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250656 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461682 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000381 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 30, 2022	PP1_strong, PP5, PM2, PS3_supporting, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 01, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 16, 2018	- -

Multiple endocrine neoplasia type 2A Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 20, 2014	- -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 05, 2024	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25887804, 17209045, 16469774]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25887804, 30927507, 26356818, 20554711, 25810047]. -

Multiple endocrine neoplasia, type 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces serine with alanine at codon 891 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported low to intermediate transforming activities and activation of kinase activity and downstream effectors (PMID: 10445857, 15753368, 25887804, 26356818). This variant has been reported in multiple individuals and families affected with multiple endocrine neoplasia type 2 and medullary thyroid carcinoma (PMID: 10024437, 15292360, 17178962, 17895320, 18062802, 20516206, 20554711, 23295303, 24449023, 26356818, 28647780, 30763276, 30927507, 31510104). This variant has been reported to segregate with disease in several pedigrees (PMID: 9398735, 10024437, 15292360, 23295303, 30927507). This variant has been identified in 3/250656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 20, 2017	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). -

Multiple endocrine neoplasia type 2B Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	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. -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -

Familial medullary thyroid carcinoma Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -

Multiple endocrine neoplasia type 4 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Multiple endocrine neoplasia, type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 02, 2021

- -

MEN2 phenotype: Unclassified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 23, 2021

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. -

Medullary thyroid carcinoma;na:Multiple endocrine neoplasia II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jul 20, 2023

PS4, PS3 -

Medullary thyroid carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.46	N;N
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.11	T;D
Sift4G	Benign	0.31	T;T
Polyphen		0.97	D;D
Vest4		0.54
MVP		0.96
MPC		0.40
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.78
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75234356; hg19: chr10-43615592; COSMIC: COSV104412347;