10-43114507-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_020975.6(RET):c.1907C>T(p.Thr636Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,456,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T636T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.24

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_020975.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.3968686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1907C>T	p.Thr636Met	missense_variant	11/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1907C>T	p.Thr636Met	missense_variant	11/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247916 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

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: 0.00000549 AC: 8 AN: 1456188 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000209

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000315 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Multiple endocrine neoplasia, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 636 of the RET protein (p.Thr636Met). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 25725622). ClinVar contains an entry for this variant (Variation ID: 405553). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects RET function (PMID: 25725622). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2021

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a damaging effect: increased cell growth, migration, and proliferation, as well as decreased contact inhibition compared to wildtype; however, these effects were reportedly milder than the p.C634R positive control (Silva 2015); This variant is associated with the following publications: (PMID: 14633923, 25725622, 30755392, 26319365, 30446652, 26678667, 27311873) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2023

The p.T636M variant (also known as c.1907C>T), located in coding exon 11 of the RET gene, results from a C to T substitution at nucleotide position 1907. The threonine at codon 636 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a woman diagnosed with sporadic medullary thyroid cancer at age 78 years of age. Functional assays measuring cell growth and proliferation, contact inhibition, and cell migration showed levels somewhat higher than wild-type, which the authors described as low-grade transforming potential (Silva AL et al. Endocrine. 2015 Jun;49(2):366-72). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

RET-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2023

The RET c.1907C>T variant is predicted to result in the amino acid substitution p.Thr636Met. This variant has been reported in an individual with thyroid cancer (Silva et al. 2015. PubMed ID: 25725622). This variant has been reported in a presumed unaffected parent from an exome trio analysis (Table S2, Ji et al. 2019. PubMed ID: 30755392). In vitro experimental studies suggest this variant may impact protein function (Silva et al. 2015. PubMed ID: 25725622). This variant is reported in 3 of ~248,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/10-43609955-C-T) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/405553/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T;.
Eigen	Benign	0.0073
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.8	L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Pathogenic	0.77
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.37	B;.;P
Vest4		0.73
MutPred		0.41		Loss of catalytic residue at T636 (P = 0.0231);.;Loss of catalytic residue at T636 (P = 0.0231);
MVP		0.69
MPC		0.26
ClinPred		0.31	T
GERP RS		3.5
Varity_R		0.090
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1035958105; hg19: chr10-43609955; COSMIC: COSV60687720;