NM_020975.6:c.1852T>A

Variant names:

• chr10-43113648-T-A
• rs76262710
• NM_020975.6:c.1852T>A

Variant summary

Our verdict is Pathogenic. The variant received 30 ACMG points: 30P and 0B. PS1_Very_Strong PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.1852T>A​(p.Cys618Ser) 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000835834: Experimental studies have shown that this missense change affects RET function (PMID:7824936, 9174404, 9230192, 9879991).; SCV004825097: Experimental studies have shown that several amino acid substitutions at this position, including p.Cys618Ser, have transforming activity in cell culture and result in intracellular retention and reduced cell surface expression of RET (PMID:9230192).". Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C618F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.95
• Publications: 114 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 30 ACMG points.

• PS1: Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000835834: Experimental studies have shown that this missense change affects RET function (PMID: 7824936, 9174404, 9230192, 9879991).; SCV004825097: Experimental studies have shown that several amino acid substitutions at this position, including p.Cys618Ser, have transforming activity in cell culture and result in intracellular retention and reduced cell surface expression of RET (PMID: 9230192).
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 22 uncertain in NM_020975.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43113649-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 24902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 10-43113648-T-A is Pathogenic according to our data. Variant chr10-43113648-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38601.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.1852T>A	p.Cys618Ser	missense	Exon 10 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.1852T>A	p.Cys618Ser	missense	Exon 10 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.1852T>A	p.Cys618Ser	missense	Exon 10 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.1852T>A	p.Cys618Ser	missense	Exon 10 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.1852T>A	p.Cys618Ser	missense	Exon 10 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.1723T>A	p.Cys575Ser	missense	Exon 10 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249068 AF XY: 0.00

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Multiple endocrine neoplasia type 2A (2)
2	-	-	Multiple endocrine neoplasia, type 2 (2)
2	-	-	not provided (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hirschsprung disease, susceptibility to, 1 (1)
1	-	-	RET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.010	D
Polyphen		0.96	D
Vest4		0.98
MutPred		0.93		Gain of disorder (P = 0.0037)
MVP		0.99
MPC		0.37
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs76262710; hg19: chr10-43609096;