10-43118458-G-T

Position:

• chr10-43118458-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 0.0980

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain Protein kinase (size 292) in uniprot entity RET_HUMAN there are 21 pathogenic changes around while only 2 benign (91%) in NM_020975.6
• 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/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.2370G>T	p.Leu790Phe	missense_variant	13/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2370G>T	p.Leu790Phe	missense_variant	13/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 34

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: 5 AN: 251150 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135854

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: 18 AN: 1461602 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727092

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: 3 AN: 152360 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74500

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.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 09, 2013	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 31, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 08, 2024	PP1_strong, PP3, PP4, PP5, PM2, PS4_moderate -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RET: PP1:Strong, PS1, PM1, PM2, PS4:Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2022	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) -

Multiple endocrine neoplasia type 2A Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 04, 2017	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]. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 05, 2024	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]. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Nov 25, 2020	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] -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 12, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 20, 2022	- -

Multiple endocrine neoplasia, type 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 24, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	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]. -

Familial medullary thyroid carcinoma Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Laan Lab, Human Genetics Research Group, University of Tartu	May 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pars Genome Lab	Mar 02, 2022	We found this variant in a 67-year-old female with Medullary thyroid carcinoma. -
Pathogenic, criteria provided, single submitter	curation	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jan 16, 2018	- -

Hirschsprung disease, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 14, 2024

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2024

The p.L790F pathogenic mutation (also known as c.2370G>T), located in coding exon 13 of the RET gene, results from a G to T substitution at nucleotide position 2370. The leucine at codon 790 is replaced by phenylalanine, an amino acid with highly similar properties. 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. This mutation was not detected in 200 controls (Berndt I et al. J. Clin. Endocrinol. Metab. 1998 Mar;83:770-4). Subsequently, this mutation has been observed in patients with MTC and/or PCC of various ethnic backgrounds, including French, Korean, and Chinese (Min JW et al. J Korean Surg Soc. 2012 Mar;82:185-9; Bihan H et al. Head Neck. 2012 Apr;34:493-8; Qi XP et al. Thyroid. 2012 Dec;22:1257-65; Pirich C et al. Wien. Klin. Wochenschr. 2012 Oct;124:723-4; Innella G et al. Cancers (Basel). 2020 Nov;12:). Family members 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 G et al. Ann. Surg. 2002 Nov;236:570-5). The American Thyroid Association has designated alterations at this codon occurring without additional RET mutations as moderate risk mutations (Wells SA et al. Thyroid. 2015 Jun;25:567-610). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is pathogenic with moderate risk for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. -

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

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

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	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.097
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
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	D
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

Other links and lift over

dbSNP: rs75030001; hg19: chr10-43613906;