rs74799832

Variant names:

• chr10-43121968-T-C
• rs74799832
• NM_020975.6:c.2753T>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.2753T>C​(p.Met918Thr) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001821474: Multiple publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant increase in tyrosine kinase activity resulting in a transforming activation of the RET proto-oncogene (example, Borrello_1995)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M918I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:44
• Conservation: PhyloP100: 8.01
• Publications: 834 publications found

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 Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001821474: Multiple publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant increase in tyrosine kinase activity resulting in a transforming activation of the RET proto-oncogene (example, Borrello_1995).; SCV004018499: Functional studies indicate this variant impacts protein function [PMID: 16715139, 9242375, 21810974].; SCV005417408: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006582341: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21810974, 9242375)."; SCV000234940: Published functional studies demonstrate a damaging effect: increased transforming ability, cellular proliferation, and tyrosine phosphorylation (Pasini 1997, Cosci 2011).; SCV000605028: Functional characterization of the variant protein indicates an increase in basal auto-phosphorylation that is further enhanced upon growth factor stimulation, with altered target specificity compared to wildtype protein (Santoro 1995, Bongarzone 1998). PMID: 7824936. PMID: 9620546; SCV000211909: Experimental studies have shown that this missense change affects RET function (PMID: 8570194, 9242375, 16715139, 21810974).; SCV005902147: Functional assays have demonstrated that RET p.(Met918Thr) induces autophosphorylation of tyrosine residues and transformation activity in fibroblasts. PMID:16715139, PMID: 9242375, PMID:10445857; SCV004721813: This variant was also shown in vitro to have transforming ability (Pasini et al. 1997. PubMed ID: 9242375; Cosci et al. 2011. PubMed ID: 21810974).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43121967-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 10-43121968-T-C is Pathogenic according to our data. Variant chr10-43121968-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.2753T>C	p.Met918Thr	missense	Exon 16 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.2753T>C	p.Met918Thr	missense	Exon 16 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.2753T>C	p.Met918Thr	missense	Exon 16 of 20	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.2753T>C	p.Met918Thr	missense	Exon 16 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.2753T>C	p.Met918Thr	missense	Exon 16 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.2489T>C	p.Met830Thr	missense	Exon 16 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251478 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000988 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	not provided (14)
10	-	-	Multiple endocrine neoplasia type 2B (10)
3	-	-	Hereditary cancer-predisposing syndrome (3)
3	-	-	Multiple endocrine neoplasia type 2A (3)
2	-	-	Familial medullary thyroid carcinoma (2)
2	-	-	Hirschsprung disease, susceptibility to, 1 (2)
2	-	-	Multiple endocrine neoplasia, type 2 (2)
1	-	-	Constipation;C0020534:Hypertelorism;C0020676:Hypothyroidism;C0039685:Tetralogy of Fallot;C0349588:Short stature;C0376480:Gingival overgrowth;C1836543:Thick vermilion border;C1844820:Joint hypermobility (1)
1	-	-	Inherited phaeochromocytoma and paraganglioma excluding NF1 (1)
1	-	-	Medullary thyroid carcinoma (1)
1	-	-	Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (1)
1	-	-	Pheochromocytoma (1)
1	-	-	RET-related disorder (1)
1	-	-	See cases (1)
1	-	-	Thyroid carcinoma, sporadic medullary (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.7	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Loss of MoRF binding (P = 0.1062)
MVP		0.97
MPC		0.84
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs74799832; hg19: chr10-43617416; COSMIC: COSV60685905;