10-43112173-G-T

Variant names:

• chr10-43112173-G-T
• rs75873440
• NM_020975.6:c.1597G>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.1597G>T​(p.Gly533Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.22

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 10-43112173-G-T is Pathogenic according to our data. Variant chr10-43112173-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13950.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	c.1597G>T	p.Gly533Cys	missense_variant	Exon 8 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1597G>T	p.Gly533Cys	missense_variant	Exon 8 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422622 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 703916

Gnomad4 AFR exome AF: 0.00

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.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Feb 15, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: significantly increased cell viability and reduced rate of apoptosis compared to wild-type (PMID: 21834681); 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; This variant is associated with the following publications: (PMID: 25624014, 23745650, 24616773, 26678667, 26839093, 24569963, 23461807, 16649977, 22676047, 18805915, 28951487, 17704047, 28137737, 30012587, 14633923, 30763276, 33340421, 14602786, 21834681) -

Dec 15, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PP4, PP5, PM2, PS4_moderate -

Apr 13, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals/families with MTC and/or pheochromocytoma including those with MEN2A (PMID: 14602786 (2003), 16649977 (2006), 17704047 (2007), 18805915 (2008), 21834681 (2011), 22676047 (2012), 23461807 (2013), 24616773 (2013), 24569963 (2014), 28951487 (2017), and 28137737 (2017)). The variant has been reported to segregate with disease and has been associated with widely variable clinical presentation and age of onset (PMIDs: 14602786 (2003), 22676047 (2012), and 23461807 (2013)). Functional studies indicate that the variant is associated with increased cell proliferation and viability, anchorage-independent growth, micronuclei formation, decreased apoptosis, and induction of liver metastases (PMID: 21834681 (2011)). Based on the available information, this variant is classified as pathogenic. -

May 05, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.1597G>T; p.Gly533Cys variant (rs75873440) is described in multiple families with medullary thyroid cancer, pheochromocytoma and multiple endocrine neoplasia type 2A (Castro 2013, Da Silva 2003, Kaldrymides 2006, Peppa 2008, Signorini 2014, Wells 2015). Functional studies show this variant increases cell growth and decreased cell death (Oliveira 2011). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 13950) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The amino acid at this position is highly conserved and computational algorithms predict this variant is deleterious (REVEL: 0.97). Considering available information, this variant is classified as pathogenic. References: Castro MR et al. Multiple endocrine neoplasia type 2A due to an exon 8 (G533C) mutation in a large North American kindred. Thyroid. 2013 Dec;23(12):1547-52. PMID: 23461807. Da Silva AM et al. A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab. 2003 88(11):5438-43. PMID: 14602786. Kaldrymides P et al. A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening. Clin Endocrinol (Oxf). 2006 May;64(5):561-6. PMID: 16649977 Oliveira MN et al. The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo. Thyroid. 2011 21(9):975-85. PMID: 21834681. Peppa M et al. Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene. Eur J Endocrinol. 2008 Dec;159(6):767-71. PMID: 18805915. Signorini PS et al. A ten-year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives. Clin Endocrinol (Oxf). 2014 80(2):235-45. PMID: 23745650. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. PMID: 25810047. -

Multiple endocrine neoplasia type 2A Pathogenic:1

Jan 12, 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: 14602786, 16649977, 18805915, 23461807, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 21834681]. -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 533 of the RET protein (p.Gly533Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A (MEN2A) (PMID: 14602786, 16649977, 18805915, 22676047, 23461807). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13950). 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 affects RET function (PMID: 21834681). For these reasons, this variant has been classified as Pathogenic. -

Familial medullary thyroid carcinoma Pathogenic:1

Feb 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 14, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G533C pathogenic mutation (also known as c.1597G>T), located in coding exon 8 of the RET gene, results from a G to T substitution at nucleotide position 1597. The glycine at codon 533 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first identified in an extensive Brazilian kindred with multiple individuals affected with medullary thyroid cancer and c-cell hyperplasia (Da Silva AM et al. J. Clin. Endocrinol. Metab. 2003 Nov; 88(11):5438-43). In a follow-up study of this kindred, one individual out of 103 carriers was found to be affected with a pheochromocytoma in addition to medullary thyroid cancer, consistent with the phenotype of MEN2A (Oliveira MN et al. Thyroid. 2011 Sep; 21(9):975-85; Signorini PS et al. Clin. Endocrinol. (Oxf) 2014 Feb; 80(2):235-45). This mutation has also been identified in multiple individuals and families of Greek ancestry affected with medullary thyroid cancer and/or pheochromocytoma, including those with the MEN2A phenotype (Kaldrymides P et al. Clin. Endocrinol. (Oxf) 2006 May; 64(5):561-6; Bethanis S et al. Hormones (Athens);6:152-6); Peppa M et al. Eur. J. Endocrinol. 2008 Dec;159:767-71; Sarika HL et al. Clin. Endocrinol. (Oxf) 2012 Dec; 77(6):857-62; Castro MR et al. Thyroid 2013 Dec; 23(12):1547-52; Saltiki K et al. Endocr Connect. 2017 Nov;6:676-684). Furthermore, functional analysis of this mutation has demonstrated that this genetic alteration confers a malignant phenotype in that mutation expressing cells were able to induce metastasis in nude mice, increase cell viability, decrease the rate of apoptosis, and decrease expression of thyroid specific genes (Oliveira MN et al. Thyroid 2011 Sep; 21(9):975-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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 for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.95
MutPred		0.78		Loss of catalytic residue at G533 (P = 0.0264);.;Loss of catalytic residue at G533 (P = 0.0264);
MVP		0.99
MPC		0.80
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.94

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: rs75873440; hg19: chr10-43607621; COSMIC: COSV99053624;