NM_020975.6:c.1900T>C

Variant names:

• chr10-43114500-T-C
• rs75076352
• NM_020975.6:c.1900T>C

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1 PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.1900T>C​(p.Cys634Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,607,602 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001338566: "In functional studies, the variant was found to have constitutive kinase activity and increased transforming ability (e.g. Cosci_2011, Santoro_1995)."" and additional evidence is available in ClinVar. 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. C634L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 7.80
• Publications: 403 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 26 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: SCV001338566: "In functional studies, the variant was found to have constitutive kinase activity and increased transforming ability (e.g. Cosci_2011, Santoro_1995)."; SCV004189806: Functional studies indicate this variant impacts protein function [PMID: 9230192, 34905813, 32293499, 21690267].; SCV000234951: Published functional studies demonstrate a damaging effect: exhibits high transforming activity (Santoro et al., 1995; Cosci et al., 2011); SCV000605036: "Consistent with these predictions, functional characterization of the variant protein indicates increased auto-phosphorylation and activation of downstream targets (Pasini 1997, Santoro 1995), resulting in enhanced malignant transformation of cells (Cosci 2011, Pasini 1997, Santoro 1995)."; SCV004220037: Furthermore, this variant has been demonstrated to result in increased transforming activity (PMIDs: 21810974 (2011), 9230192 (1997), 7824936 (1995)), and significantly increased kinase activity in vitro (PMID: 8570194 (1995)).; SCV000213872: This mutation affects the extracellular domain of the RET protein, a receptor tyrosine kinase, and leads to ligand-independent receptor dimerization and constitutive RET signaling (Mulligan LM Nat. Rev. Cancer. 2014 Mar;14(3):173-86, Santoro et al. Science. 1995 Jan;267(5196):381-3).; SCV000658427: Experimental studies have shown that this missense change affects RET function (PMID: 7824936, 8099202, 8570194, 12000816, 15472167, 21765987, 21810974, 25440022).; SCV004838638: Functional studies have demonstrated that this variant protein has constitutive kinase activity and increases transforming ability in transfected cells (PMID: 7824936, 8570194, 15472167, 21810974).; SCV004847566: "In vitro functional studies in transfected cells show that the p.Cys634Arg variant exhibits high transforming activity (Orgiana 2004 PMID: 15472167, Santoro 1995 PMID: 7824936, Cosci 2011 PMID: 21810974, Borrello 1995 PMID: 8570194 )"; SCV005362621: Functional studies support its pathogenicity, and demonstrate the p.Cys634Arg variant to be a gain-of-function substitution that results in constitutive RET activity (Pasini, 1997. PubMed ID: 9242375; Cosci, 2011. PubMed ID: 21810974).; SCV005416704: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 36 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 chr10-43114500-TG-CT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 820303.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 10-43114500-T-C is Pathogenic according to our data. Variant chr10-43114500-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13917.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.1900T>C	p.Cys634Arg	missense	Exon 11 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.1900T>C	p.Cys634Arg	missense	Exon 11 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.1900T>C	p.Cys634Arg	missense	Exon 11 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.1900T>C	p.Cys634Arg	missense	Exon 11 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.1900T>C	p.Cys634Arg	missense	Exon 11 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000615310.5	TSL:5	c.1504T>C	p.Cys502Arg	missense	Exon 9 of 17	ENSP00000480088.2	A0A087WWB1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247534 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: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455718 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724440

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151884 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74168

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41330

American (AMR) AF: 0.000131 AC: 2 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
5	-	-	Multiple endocrine neoplasia type 2A (5)
3	-	-	Multiple endocrine neoplasia, type 2 (3)
2	-	-	Hirschsprung disease, susceptibility to, 1 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma (1)
1	-	-	Pheochromocytoma (1)
1	-	-	RET-related disorder (1)
1	-	-	Thyroid gland carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.93		Loss of stability (P = 0.0824)
MVP		0.98
MPC		0.53
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.95
gMVP		0.98
Mutation Taster		=0/100	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: rs75076352; hg19: chr10-43609948; COSMIC: COSV60686093;