rs377767407

chr10-43114494-G-Achr10-43114494-G-Cchr10-43114494-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_020975.6(RET):c.1894G>A(p.Glu632Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,607,222 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E632D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:1
• Conservation: PhyloP100: 7.90

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 3 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1894G>A	p.Glu632Lys	missense_variant	11/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1894G>A	p.Glu632Lys	missense_variant	11/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000971 AC: 24 AN: 247226 Hom.: 0 AF XY: 0.000112 AC XY: 15 AN XY: 134056

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000433 AC: 63 AN: 1455192 Hom.: 0 Cov.: 33 AF XY: 0.0000497 AC XY: 36 AN XY: 724220

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2019	The RET c.1894G>A; p.Glu632Lys variant has been described in individuals affected with medullary thyroid cancer (MTC), Hirschsprung's disease, or pheochromocytoma (Carter 2012, Frank-Raue 2007, Han 2006, Romei 2015). It is reported as a variant of uncertain significance multiple times in ClinVar (Variation ID: 24920), and is observed in the general population at an overall frequency of 0.01% (24/247226 alleles) in the Genome Aggregation Database. The glutamic acid at codon 632 is moderately conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is tolerated. Due to limited information, the clinical significance of this variant cannot be determined with certainty. REFERENCES Carter TC et al. Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. J Hum Genet. 2012 Aug;57(8):485-93. Frank-Raue K et al. Change in the spectrum of RET mutations diagnosed between 1994 and 2006. Clin Lab. 2007;53(5-6):273-82. Han ZY et al. Mutation screening of RET proto-oncogene in Chinese sporadic patients with pheochromocytoma. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006 Jun;23(3):320-2. Romei C et al. Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? Clin Endocrinol (Oxf). 2015 Jun;82(6):892-9. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17605401, 21479187, 16767674, 25440022, 34169762, 34570441, 31510104, 22648184, 30217742, 31159747, 14633923) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RET: PM1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 12, 2021	The p.Glu632Lys variant in RET has been reported in 2 individuals with Hirschsprung's disease, 1 individual with medullary thyroid carcinoma, and 1 individual tested for a hereditary cancer panel (Carter 2011 PMID: 22648184, Romei 2015 PMID: 25440022, Tang 2018 PMID: 30217742, Tsaousis 2019 PMID: 31159747). It has also been identified in 0.05% (14/30612) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4. -

Multiple endocrine neoplasia type 2A Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 18, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	Jun 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 14, 2015	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 09, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

Multiple endocrine neoplasia type 2B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 14, 2015

- -

Multiple endocrine neoplasia, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 632 of the RET protein (p.Glu632Lys). This variant is present in population databases (rs377767407, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 17605401, 22648184, 25440022, 30217742, 31510104). ClinVar contains an entry for this variant (Variation ID: 24920). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.16	T;D;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.71	P;.;D
Vest4		0.76
MutPred		0.81		Gain of methylation at E632 (P = 0.0126);.;Gain of methylation at E632 (P = 0.0126);
MVP		0.87
MPC		0.23
ClinPred		0.12	T
GERP RS		3.6
Varity_R		0.15
gMVP		0.76

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: rs377767407; hg19: chr10-43609942; COSMIC: COSV60688897;