Menu
GeneBe

rs75996173

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2_SupportingPM5PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.1901G>A(p.Cys634Tyr) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C634L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

11
6
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26

Conservation

PhyloP100: 9.74

Links

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_020975.6
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr10-43114501-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
?
Variant 10-43114501-G-A is Pathogenic according to our data. Variant chr10-43114501-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43114501-G-A is described in Lovd as [Pathogenic]. Variant chr10-43114501-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RETNM_020975.6 linkuse as main transcriptc.1901G>A p.Cys634Tyr missense_variant 11/20 ENST00000355710.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.1901G>A p.Cys634Tyr missense_variant 11/205 NM_020975.6 P4P07949-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000404
AC:
1
AN:
247574
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134198
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1455706
Hom.:
0
AF XY:
0.00000276
AC XY:
2
AN XY:
724436
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:26
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2a Pathogenic:8
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 18, 2023This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192, 21834681]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26732158, 17188172, 34439168, 20801952, 33827484, 25810047]. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 18, 2019Variant summary: RET c.1901G>A (p.Cys634Tyr) results in a non-conservative amino acid change located in the extracellular domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247574 control chromosomes. c.1901G>A has been well reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A (example Chiefari_1998, Frank-Raue_2006). These data indicate that the variant is strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a gain of function mechanism due to activation of the RET proto-oncogene (example Santoro_1995). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)May 21, 2023- -
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingCounsylAug 30, 2017- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 09, 2002- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterSep 01, 2021- -
not provided Pathogenic:7
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 08, 2023- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 29, 2020The RET c.1901G>A;p.Cys634Tyr variant (rs75996173) is reported in the literature in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (American Thyroid Association Guidelines Task Force 2009, Punales 2003, Wells 2015). This variant is found on a single chromosome in the Genome Aggregation Database (1/247574 alleles), indicating it is not a common polymorphism. The cysteine at codon 634 is highly conserved, and other amino acid substitutions at this codon (Arg, Gly, Phe, Ser, Trp) are considered causative for MEN2A (Wells 2015). Functional characterization of the p.Cys364Tyr variant and other missense variants at the same codon (p.Cys634Arg, p.Cys634Trp) indicates increased auto-phosphorylation and activation of downstream targets (Santoro 1995), resulting in enhanced malignant transformation of cells (Cosci 2011, Santoro 1995). Based on available information, the p.Cys634Tyr variant is considered to be pathogenic. References: American Thyroid Association Guidelines Task Force et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun;19(6):565-612. Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011 Sep 20;18(5):603-12. Punales MK et al. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003 Jun;88(6):2644-9. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381-3. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 14, 2021The RET c.1901G>A (p.Cys634Tyr) variant has been reported in the published literature in multiple individuals with MEN2A and/or FMTC (PMID: 7835899 (1994), 9950371 (1999), 12000816 (2002), 21765987 (2011), 25810047 (2015), 26732158 (2016), 28099363 (2017), 33167350 (2020)). A functional study found the variant has a damaging effect on RET function (PMID: 7824936 (2015)). The frequency of this variant in the general population, 0.000004 (1/247574 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 24, 2023Published functional studies demonstrate a damaging effect: high transforming ability, constitutive kinase activation (Santoro 1995, Ito 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(Cys380Tyr); This variant is associated with the following publications: (PMID: 12711285, 8797874, 9146685, 23723040, 19062722, 27558615, 25515555, 26254625, 29133048, 29656518, 23330657, 7835899, 21765987, 7824936, 8099202, 15858153, 8626834, 21054478, 16314641, 17895320, 24716929, 12000816, 7874109, 20080836, 26732158, 28099363, 26758973, 26572832, 26876062, 27539324, 23868299, 11987030, 30139385, 29197744, 7881414, 9230192, 28469506, 30113649, 21655256, 18063059, 12686527, 9950371, 7860065, 16099853, 11524247, 19240193, 7914213, 7491519, 12604374, 9820617, 9699127, 31062739, 30122763, 16158949, 20516206, 29625052, 31510104, 32989896, 8909322, 18096130, 9497883, 8984233, 35627249, 28152038, 30763276, 9706252, 25545346, 33340421, 33219105, 35418818, 14633923) -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncMay 14, 2021The 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 clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. The American Thyroid Association has placed this variant into the ATA-H category, formerly known as level C, for having a high risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging. -
Multiple endocrine neoplasia, type 2b Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023The family RET mutation (C634Y) was detected in this blood specimen. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909) with 22 submissions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 7824936). 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: 8099202, 12000816, 21765987). Therefore, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingSuma Genomics-- -
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Pheochromocytoma Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou UniversityOct 06, 2021- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 09, 2002- -
Multiple endocrine neoplasia type 4 Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Multiple endocrine neoplasia, type 1 Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Jul 14, 2015- -
Multiple endocrine neoplasia, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 25, 2022This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 7824936). 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: 8099202, 12000816, 21765987). 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. -
Medullary thyroid carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2022The p.C634Y pathogenic mutation (also known as c.1901G>A) is located in coding exon 11 of the RET gene. This alteration results from a G to A substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C634Y mutation has been reported in several unrelated families diagnosed with MEN2A and/or familial medullary thyroid carcinoma (FMTC) (Mulligan et al. Nature. 1993;363:458-460; Marsh DJ et al. Genomics. 1994;23(2):477-479; Hedayati et al. J Thyroid Res. 2011;2011:264248; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). Amino acid position 634 is a well described mutation hot spot associated with MEN2A/FMTC. Studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Neumann HP et al. N. Engl. J. Med. 2002;346:1459-66, Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003;138:409-16). Revised American Thyroid Association Guidelines categorize the p.C634Y alteration as high risk (ATA-H) and recommend surveillance and prophylactic surgery in early childhood (Wells SA et al. Thyroid 2015 Jun;25(6):567-610). Of note, this alteration has been referred to as p.C380Y (c.1832G>A) and p.C634Y (c.2096G>A) in the published literature. Based on the available evidence, p.C634Y is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.73
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.57
Cadd
Pathogenic
29
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;D;.
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.71
T;T;T
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.7
M;.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.79
T
PROVEAN
Pathogenic
-7.0
D;D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0010
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.99
MutPred
0.95
Gain of catalytic residue at C634 (P = 0.0096);.;Gain of catalytic residue at C634 (P = 0.0096);
MVP
0.97
MPC
0.45
ClinPred
0.98
D
GERP RS
3.6
Varity_R
0.86
gMVP
0.96

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs75996173; hg19: chr10-43609949; COSMIC: COSV60688821; API