rs75996173

Variant names:

• chr10-43114501-G-A
• rs75996173
• NM_020975.6:c.1901G>A
• RET p.Cys634Tyr

Your query was ambiguous. Multiple possible variants found:

• chr10-43114501-G-A
• chr10-43114501-G-C
• chr10-43114501-G-T

GermlineCancer (beta)

Variant summary

Our verdict is

Pathogenic

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 16 classification points (ACMG Germline Pathogenicity v2019): 16P and 0B. PS3PM1PM2PM5PP3_ModeratePP5_Strong

The NM_020975.6(RET):c.1901G>A (p.Cys634Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,455,706 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.74). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000053074: "At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a gain of function mechanism due to activation of the RET proto-oncogene (example Santoro_1995)."" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C634F: Pathogenic (ClinVar VariationId 2025097, 1 star) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org) with 45 samples affected at this amino acid position. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 9.74
• Publications: 253 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: Orphanet, G2P
• multiple endocrine neoplasia type 2A

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

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

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 16 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000053074: "At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a gain of function mechanism due to activation of the RET proto-oncogene (example Santoro_1995)."; SCV004018493: Functional studies indicate this variant impacts protein function [PMID: 9230192, 21834681].; SCV005382535: Functional characterization of the p.Cys634Tyr variant and other missense variants at the same amino acid position (p.Cys634Arg, p.Cys634Trp) indicated increased auto-phosphorylation and activation of downstream targets, resulting in enhanced malignant transformation of cells (Cosci et al., 2011, Santoro et al., 1995).; SCV000234934: Published functional studies demonstrate a damaging effect: high transforming ability, constitutive kinase activation (Santoro 1995, Ito 1997).; SCV000605016: Functional characterization of the p.Cys364Tyr variant and other missense variants at the same codon (p.Cys634Arg, p.Cys634Trp) indicates increased auto-phosphorylation and activation of downstream targets (Santoro 1995), resulting in enhanced malignant transformation of cells (Cosci 2011, Santoro 1995). PMID: 7824936. PMID: 21810974. PMID: 19469690.; SCV000842752: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 7824936, 9230192); SCV002047250: A functional study found the variant has a damaging effect on RET function (PMID: 7824936 (2015)).; SCV004015290: Experimental studies have shown that this missense change affects RET function (PMID: 7824936).; SCV000543790: Experimental studies have shown that this missense change affects RET function (PMID: 7824936).; SCV005361904: Functional studies have shown this variant and other amino acid changes at this position result in increased auto-phosphorylation and activation of downstream targets which enhances malignant transformation of cells (Santoro M et al. 1995. PubMed ID: 7824936; Cosci B et al. 2011. PubMed ID: 21810974).
• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 8 pathogenic, 2 benign (OR vs. background: 17.0).
• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (base 0.0001, raised to 0.000122 by highest known P/LP ClinVar AF 0.000122) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.C634F: Pathogenic (ClinVar VariationId 2025097, 1 star)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (27/27 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.1901G>A	p.Cys634Tyr	missense	Exon 11 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.1901G>A	p.Cys634Tyr	missense	Exon 11 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.1901G>A	p.Cys634Tyr	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.1901G>A	p.Cys634Tyr	missense	Exon 11 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.1901G>A	p.Cys634Tyr	missense	Exon 11 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000615310.5	TSL:5	c.1505G>A	p.Cys502Tyr	missense	Exon 9 of 17	ENSP00000480088.2	A0A087WWB1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247574 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455706 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724436

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

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47316

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111978

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Multiple endocrine neoplasia type 2A (9)
7	-	-	not provided (7)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Hirschsprung disease, susceptibility to, 1 (2)
2	-	-	Multiple endocrine neoplasia type 2B (2)
2	-	-	Pheochromocytoma (2)
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	-	-	Multiple endocrine neoplasia, type 2 (1)
1	-	-	RET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.86
gMVP		0.96
Mutation Taster		=4/96	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs75996173;

hg19: chr10-43609949;

COSMIC: COSV60688821;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar