chr10-43113654-T-A

Position:

• chr10-43113654-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.1858T>A​(p.Cys620Ser) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C620F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.52

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43113655-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 10-43113654-T-A is Pathogenic according to our data. Variant chr10-43113654-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.1858T>A	p.Cys620Ser	missense_variant	10/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1858T>A	p.Cys620Ser	missense_variant	10/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces cysteine with serine at codon 620 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with MEN2/familial medullary thyroid carcinoma (PMID: 7849720, 11238493) or suspected MEN2A case (PMID: 14718397). Another variant with the same protein change is known to be disease-causing (c.1859G>C, p.Cys620Ser; ClinVar Variation ID: 13943). Mutations at this codon have been categorized by the American Thyroid Association as having moderate risk for MTC and is associated with a pheochromocytoma incidence rate of 13%-24% (PMID: 25810047). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 31, 2023	This missense variant replaces cysteine with serine at codon 620 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with MEN2/familial medullary thyroid carcinoma (PMID: 7849720, 11238493) or suspected MEN2A case (PMID: 14718397). Another variant with the same protein change is known to be disease-causing (c.1859G>C, p.Cys620Ser; ClinVar Variation ID: 13943). Mutations at this codon have been categorized by the American Thyroid Association as having moderate risk for MTC and is associated with a pheochromocytoma incidence rate of 13%-24% (PMID: 25810047). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 07, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys620 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7874109, 8909322, 16705552, 20979234, 21765987). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RET function (PMID: 9230192). 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. ClinVar contains an entry for this variant (Variation ID: 38602). This missense change has been observed in individuals with multiple endocrine neoplasia type 2 and/or Hirschsprung disease (PMID: 10777380, 11471675, 14517954). It has also been observed to segregate with disease in related individuals. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 620 of the RET protein (p.Cys620Ser). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2018

The p.C620S pathogenic mutation (also known as c.1858T>A), located in coding exon 10 of the RET gene, results from a T to A substitution at nucleotide position 1858. The cysteine at codon 620 is replaced by serine, an amino acid with dissimilar properties. This pathogenic mutation has been reported in the germline of a 44 year old Italian individual diagnosed with a unilateral pheochromocytoma and a family history consistent with MEN2 (Iacobone M et al. Surgery. 2011 Dec;150:1194-201). In addition, this mutation is located in codon 620, which encodes part of the extracellular cysteine rich domain and is a well-described mutation hotspot site. Mutations at this codon have been categorized by the American Thyroid Association as having moderate risk for MTC and is associated with a pheochromocytoma incidence rate of 13%–24% (Wells SA et al. Thyroid. 2015 Jun;25:567-610). Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.92
Sift	Benign	0.040	D;D;D
Sift4G	Benign	0.074	T;D;T
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.94		Gain of disorder (P = 0.0024);.;Gain of disorder (P = 0.0024);
MVP		1.0
MPC		0.66
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.84
gMVP		0.98

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: rs77316810; hg19: chr10-43609102; COSMIC: COSV60689083;