10-43118458-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.2370G>T(p.Leu790Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,962 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 (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24O:1

Conservation

PhyloP100: 0.0980

Variant links:

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]

RET links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

PP5

Variant 10-43118458-G-T is Pathogenic according to our data. Variant chr10-43118458-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 38612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43118458-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.2370G>T	p.Leu790Phe	missense_variant	Exon 13 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.2370G>T	p.Leu790Phe	missense_variant	Exon 13 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251150

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135854

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461602

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:11

Aug 31, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.2370G>T, p.Leu790Phe variant (rs75030001) has been reported in multiple individuals with medullary thyroid carcinoma (MTC), segregates with disease in families with MTC, and has also been described in individuals with pheochromocytoma (Berndt 1998, Bihan 2011, Bihan 2013, Fitze 2002, Fussey 2021, Min 2012). This variant is listed as pathogenic in ClinVar (Variation ID: 38612) and is observed in the general population at a low overall frequency of 0.002% (5/251,150 alleles) in the Genome Aggregation Database. The leucine at codon 790 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.733). Additionally, another variant that results in the same amino acid change (c.2370G>C; p.Leu790Phe) has been reported in individuals affected with MTC (Berndt 1998). Based on available information, the c.2370G>T variant is considered pathogenic. References: Berndt I et al. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. 1998;J Clin Endocrinol Metab. 83(3):770-4. PMID: 9506724 Bihan H et al. Role of prophylactic thyroidectomy in RET 790 familial medullary thyroid carcinoma. Head Neck. 2012 Apr;34(4):493-8. PMID: 21688339. Bihan H et al. The clinical spectrum of RET proto-oncogene mutations in codon 790. 2013;Eur J Endocrinol. 169(3):271-6. PMID: 23756355. Fitze G et al. Various penetrance of familial medullary thyroid carcinoma in patients with RET protooncogene codon 790/791 germline mutations. Ann Surg. 2002 Nov;236(5):570-5. PMID: 12409662. Fussey JM et al. Diagnostic RET genetic testing in 1,058 index patients: A UK centre perspective. Clin Endocrinol (Oxf). 2021 Aug;95(2):295-302. PMID: 33340421. Min J et al. Bilateral adrenal pheochromocytoma with a germline L790F mutation in the RET oncogene. J Korean Surg Soc. 2012 Mar;82(3):185-9. PMID: 22403753. -

Jul 08, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PP4, PP5, PM2, PS4_moderate -

May 09, 2013

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, it has been reported in multiple individuals with Familial Medullary Thyroid Cancer (FMTC) or MEN 2A (PMID: 9506724 (1998), 12409662 (2002), 18062802 (2008), 18248648 (2008), 21688339 (2012), 23756355 (2013), 26254625 (2016)). This variant is described by the American Thyroid Association (ATA) as associated with moderate risk of aggressive MTC (PMID: 25810047 (2015)). Based on the available information, the variant is classified as pathogenic. -

May 22, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9506724, 26868437, 29175871, 21810974, 23756355, 22403753, 12193298, 12409662, 18062802, 12490841, 21688339, 9167962, 22965292, 26254625, 24699901, 27379493, 21626080, 26678667, 27809725, 28018431, 28609830, 28698976, 29378779, 29341155, 29590403, 30355600, 30877234, 31510104, 30787465, 31447099, 15455293, 34426522, 33087929, 14633923) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RET: PP1:Strong, PS1, PM1, PM2, PS4:Moderate -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 11, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia type 2A

Pathogenic:5

Nov 25, 2020

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Leu790Phe variant in the RET gene has been previously reported in at least 50 individuals with medullary thyroid cancer (Berndt et al., 1998; Brauckhoff et al., 2002; Gimm et al., 2002; Bihan et al., 2012; Larsen et al., 2020), as well as in individuals with pheochromocytoma (Berndt et al., 1998; Min et al., 2012), and segregated with disease in several families (Berndt et al., 1998; Bihan et al., 2012). This variant has been classified as a moderate risk allele primarily associated with the FMTC and MEN2A phenotypes (Loveday et al., 2018). This variant has been identified in 5/251,150 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Additionally, a different nucleotide change (c.2370G>C) resulting in an identical amino change has been previously reported. The c.2370G>C (p.Leu790Phe) variant is pathogenic and is expected to result in a similar disruption to protein function as c.2370G>T. Computational tools predict that p.Leu790Phe is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Leu790Phe variant as pathogenic for autosomal dominant multiple endocrine neoplasia type 2 based on the information above. [ACMG evidence codes used: PS1; PS4; PM2; PP3] -

May 12, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RET c.2370G>T (p.Leu790Phe) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) 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 2e-05 in 251550 control chromosomes (gnomAD and Berndt_1998). c.2370G>T has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A/Familial Medullary Thyroid Cancer and has been found to segregate with disease within families (e.g. Berndt_1998, Gimm_2002, Romei_2010, Bihan_2011). These data indicate that the variant is very likely to be associated with disease. Another variant resulting in the same amino acid change, c.2370G>C (p.Leu790Phe) has also been reported in affected individuals (e.g. Gimm_2002), providing additional evidence supporting a pathogenic role. The following publications have been ascertained in the context of this evaluation (PMID: 9506724, 20516206, 21688339, 12490841). Multiple submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and the majority have classified the variant as pathogenic (n=13), with one submitter classifying it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 04, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2370G>C (p.Leu790Phe) variant has been reported in patients with familial and sporadic medullary thyroid cancer [PMID 9506724, 22965292, 21810974] and pheochromocytoma [PMID 22403753]. Segregation of the variant with medullary thyroid carcinoma was reported in several families [PMID 9506724, 22965292]. Another variant affecting the same amino acid at position 790 (c.2370G>T) and leading to the same amino acid change (p.Leu790Phe) has also been reported in patients with sporadic medullary thyroid cancer and pheochromocytoma [PMID 9506724]. A retrospective study showed that patients carrier for this p.Leu790Phe change have a non-aggressive form or slow evolving multiple endocrine neoplasia type 2 [PMID 23756355]. The role of prophylactic thyroidectomy in patients carriers for this p.Leu790Phe variant was also evaluated [PMID 21688339]. Two carriers from this study were over 70 years of age and were asymptomatic. Thus, the authors concluded that, for carriers of this p.Leu790Phe variant, a case-by-case decision instead of systematic prophylactic thyroidectomy should be discussed [PMID 21688339]. This variant was observed in two individuals at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/10-43613906-G-T).This variant is highly conserved in mammals and while not clinically validated, computer-based algorithms predict this p.Leu790Phe change to be deleterious. This variant is thus classified as pathogenic. This variant is also considered medically actionable [ACMG 59, PMID 27854360]. -

Jan 05, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 33827484, 33167350, 12490841, 12409662, 9506724, 25810047]. -

Jul 20, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 2

Pathogenic:3

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 790 of the RET protein (p.Leu790Phe). This variant is present in population databases (rs75030001, gnomAD 0.007%). This missense change has been observed in individual(s) with medullary thyroid carcinoma and/or pheochromocytoma (PMID: 9506724, 12409662, 12490841, 21688339, 22403753, 22965292, 23756355). Notably, the p.Leu790Phe variant is associated with a less aggressive form of multiple endocrine neoplasia type 2, with fewer cases of pheochromocytoma compared to other pathogenic RET variants (PMID: 23756355, 21688339, 12490841). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38612). 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 does not substantially affect RET function (PMID: 21810974). For these reasons, this variant has been classified as Pathogenic. -

Aug 24, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with phenylalanine at codon 790 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). A functional study has reported that this variant protein does not confer significant cell transforming activity in transfected ex vivo cells (PMID: 21810974). This variant has been reported in multiple individuals affected with medullary thyroid cancer (PMID: 9506724, 12409662, 12490841, 18062802, 26254625, 27379493, 32411094, 33827484) and an individual affected with bilateral adrenal pheochromocytoma (PMID: 22403753). This variant is also reported to segregate with medullary thyroid cancer in individuals from over 10 families (PMID: 9506724, 12409662, 33827484). This variant has been described as a low- to moderate-risk variant for medullary thyroid cancer based on the American Thyroid Association stratification (PMID: 23756355, 33167350, 33827484). This variant has been identified in 5/251150 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Familial medullary thyroid carcinoma

Pathogenic:3

Jan 16, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 02, 2022

Pars Genome Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We found this variant in a 67-year-old female with Medullary thyroid carcinoma. -

May 01, 2021

Laan Lab, Human Genetics Research Group, University of Tartu

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hirschsprung disease, susceptibility to, 1

Pathogenic:1

Feb 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jan 07, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2370G>T (p.L790F) alteration is located in exon 13 (coding exon 13) of the RET gene. This alteration results from a G to T substitution at nucleotide position 2370, causing the leucine (L) at amino acid position 790 to be replaced by a phenylalanine (F). pathogenic with moderate risk for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/251150) total alleles studied. The highest observed frequency was 0.006% (1/16228) of African alleles. This mutation has been described in a German family with multiple endocrine neoplasia type 2 (MEN2); the index case and three other affected family members all had medullary thyroid cancer (MTC) and a pheochromocytoma (PCC) and two other affected family members had medullary thyroid cancer only (Berndt, 1998). Subsequently, this mutation has been observed in individuals with MTC and/or PCC of various ethnic backgrounds, including French, Korean, and Chinese (Min, 2012; Bihan, 2012; Pirich, 2012; Qi, 2012; Innella, 2020). Relatives of two unrelated cases of MTC who underwent presymptomatic testing for this mutation and tested positive elected to undergo prophylactic thyroidectomy and were found to have c-cell hyperplasia at age 9 and age 16 (Fitze, 2002). The American Thyroid Association has designated alterations at this codon occurring without additional RET mutations as moderate risk mutations (Wells, 2015). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Multiple endocrine neoplasia type 2A;C3888239:Hirschsprung disease, susceptibility to, 1

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 11-04-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.097

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.94

Gain of methylation at K789 (P = 0.0267);Gain of methylation at K789 (P = 0.0267);

MVP

0.98

MPC

0.81

ClinPred

0.89

GERP RS

0.96

Varity_R

0.83

gMVP

0.83

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over