10-43118458-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.2370G>C(p.Leu790Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,602 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

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 16 ACMG points.

PS1

Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 10-43118458-G-C is Pathogenic according to our data. Variant chr10-43118458-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251150

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461602

Hom.:

Cov.:

AF XY:

0.00000275

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 2A

Pathogenic:3

Dec 26, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 18, 2023

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: 28946813, 33827484, 33167350, 12490841, 12409662, 9506724, 25810047]. -

Familial medullary thyroid carcinoma

Pathogenic:3

Jan 20, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 15, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 2

Pathogenic:1

Nov 03, 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 0.0009%). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 9506724, 12409662, 12490841, 14561794, 16868135, 18062802, 20516206, 20833330, 21688339, 22965292, 23756355, 25767701). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13935). 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. -

not provided

Pathogenic:1

Nov 21, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate transforming activity similar to wildtype (PMID: 21810974); This variant is associated with the following publications: (PMID: 23756355, 21810974, 19469690, 22403753, 9167962, 14633923, 33167350, 20516206, 16314641, 28125078, 30355600, 9506724, 33827484, 17895320, 21054478, 29656518, 29590403, 28946813, 30624503, 12490841, 11238493, 25810047) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 30, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L790F pathogenic mutation (also known as c.2370G>C), located in coding exon 13 of the RET gene, results from a G to C 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 identified in three brothers diagnosed with medullary thyroid cancer (MTC); three unaffected family members tested negative for this alteration and did not display any clinical or biochemical features of Multiple Endocrine Neoplasia type 2A (MEN2A) (Berndt I et al. J Clin Endocrinol Metab, 1998 Mar;83:770-4). This variant has also been identified in multiple unrelated individuals with a personal history of MTC (Machens A et al. Hum Mutat, 2018 06;39:860-869). Another variant at this position resulting in the same amino acid change (c.2370G>T) has been identified in individuals and families with MTC and/or pheochromocytoma (PCC) and is classified as a moderate risk mutation (Berndt I et al. J. Clin. Endocrinol. Metab. 1998 Mar;83:770-4; 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). In addition to the clinical data presented in the literature, this allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is predicted to be deleterious by in silico analysis. 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). Based on the supporting evidence, this variant is expected to be a pathogenic mutation with moderate risk of MEN2; however, its clinical significance for Hirschsprung disease is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.37

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

0.97

D;D

MetaSVM

Uncertain

0.25

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

0.98

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