10-43114501-G-T

Position:

chr10-43114501-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.1901G>T(p.Cys634Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,706 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. 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: 6.9e-7 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.74

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 22 ACMG points.

PS1

Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2025097

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 in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-43114500-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 13908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 10-43114501-G-T is Pathogenic according to our data. 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. Variant chr10-43114501-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6 linkuse as main transcript	c.1901G>T	p.Cys634Phe	missense_variant	11/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.1901G>T	p.Cys634Phe	missense_variant	11/20	5	NM_020975.6	P4	P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247574

Hom.:

AF XY:

0.00

AC XY:

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:

6.87e-7

AC:

AN:

1455706

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724436

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 2A

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 14, 2024	Criteria applied: PS4,PM5_STR,PM1,PM2_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 31, 2023	phenylalanine, which is neutral and non-polar, at codon 634 of the RET protein (p.Cys634Phe). This variant is present in population databases (rs75996173, gnomAD 0.007%). This misscnse change has been observed in individuals with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid cancer (MTC) and7or phcochromocytoma (PMID: 8099202, 12000816, 16865647, 17895320, 18062802, 20739875, 24684035, 24716929, 25440022, 25628771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13911). Algorithms developed to predict the effect of misscnse changes on protein structure and function are either unavailable or do not agree on the potential impact of this misscnse change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class CO"). 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, 25440022). For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the RET gene are associated with multiple endocrine neoplasia type 2. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 09, 2002	- -

Pheochromocytoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 09, 2002

- -

Multiple endocrine neoplasia, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 634 of the RET protein (p.Cys634Phe). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individuals with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid cancer (MTC) and/or pheochromocytoma (PMID: 8099202, 12000816, 16865647, 17895320, 18062802, 20739875, 24684035, 24716929, 25440022, 25628771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13911). 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 tolerated. 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, 25440022). 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. -

Familial medullary thyroid carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 09, 2002

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 03, 2021

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2023

The p.C634F pathogenic mutation (also known as c.1901G>T), located in coding exon 11 of the RET gene, results from a G to T substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This mutation has been identified in multiple individuals meeting clinical diagnostic criteria for multiple endocrine neoplasia type 2A (MEN2A) and has been demonstrated to segregate with disease within several MEN2A families (Saito T et al. Am J Med Sci. 2010 Oct;340(4):329-31; Jesic M et al. Srp Arh Celok Lek. 2014 Jan-Feb;142(1-2):72-4; Masbi H et al. Asian Pac J Cancer Prev. 2014;15(5):2027-33; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23). This mutation occurs at a known hotspot and 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). Per the American Thyroid Association Guideline Taskforce of 2009 (ATA), this mutation has screening and prophylactic recommended interventions beginning in early childhood. 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 interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.4

D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.92

MutPred

0.96

Loss of catalytic residue at T636 (P = 0.1065);.;Loss of catalytic residue at T636 (P = 0.1065);

MVP

0.97

MPC

0.41

ClinPred

0.99

GERP RS

3.6

Varity_R

0.89

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.

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