NM_020975.6:c.1859G>C

Variant names:

• chr10-43113655-G-C
• rs77503355
• NM_020975.6:c.1859G>C
• RET p.Cys620Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_SupportingO7_Supporting

The NM_020975.6(RET):c.1859G>C (p.Cys620Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The gene RET is a known oncogene (CancerMine: 12 TSG, 1727 oncogene, 174 driver citations). The gene RET is a cancer driver gene (CancerMine: 12 TSG, 1727 oncogene, 174 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: 8.13). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001579533: Experimental studies have shown that this missense change affects RET function (PMID:9230192)." 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.C620R: Pathogenic (ClinVar VariationId 13915, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.C620= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 549782) 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)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.13
• Publications: 9 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: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 6 pathogenic, 2 benign (OR vs. background: 13.0); Variant does not impact splicing — splice-hotspot path not applicable

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.1859G>C p.Cys620Ser	missense	Exon 10 of 20	Prot: NP_066124.1 UniProt:
	RET NM_001406743.1		c.1859G>C p.Cys620Ser	missense	Exon 10 of 21	Prot: NP_001393672.1 UniProt:
	RET NM_001406744.1		c.1859G>C p.Cys620Ser	missense	Exon 10 of 20	Prot: NP_001393673.1

RET NM_020975.6

MANE Select

HGVSc / HGVSpc.1859G>Cp.Cys620Ser

Exon rankExon 10 of 20

missense

Prot: NP_066124.1UniProt: P07949-1

RET NM_001406743.1

HGVSc / HGVSpc.1859G>Cp.Cys620Ser

Exon rankExon 10 of 21

missense

Prot: NP_001393672.1UniProt: P07949-1

RET NM_001406744.1

HGVSc / HGVSpc.1859G>Cp.Cys620Ser

Exon rankExon 10 of 20

missense

Prot: NP_001393673.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RET ENST00000355710.8	TSL:5MANE Select	c.1859G>C p.Cys620Ser	missense	Exon 10 of 20	Prot: ENSP00000347942.3 UniProt:
	RET ENST00000340058.6	TSL:1	c.1859G>C p.Cys620Ser	missense	Exon 10 of 19	Prot: ENSP00000344798.4 UniProt:
	RET ENST00000713926.1		c.1730G>C p.Cys577Ser	missense	Exon 10 of 19	Prot: ENSP00000519223.1 UniProt:

RET ENST00000355710.8

TSL:5MANE Select

HGVSc / HGVSpc.1859G>Cp.Cys620Ser

Exon rankExon 10 of 20

missense

Prot: ENSP00000347942.3UniProt: P07949-1

RET ENST00000340058.6

TSL:1

HGVSc / HGVSpc.1859G>Cp.Cys620Ser

Exon rankExon 10 of 19

missense

Prot: ENSP00000344798.4UniProt: P07949-2

RET ENST00000713926.1

HGVSc / HGVSpc.1730G>Cp.Cys577Ser

Exon rankExon 10 of 19

missense

Prot: ENSP00000519223.1UniProt: A0AAQ5BH28

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122592	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Multiple endocrine neoplasia, type 2 (2)
1	-	-	Familial medullary thyroid carcinoma (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	MEN2 phenotype: Unclassified (1)
1	-	-	Multiple endocrine neoplasia type 2A (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-7.9
GPN-Star score	N/A	7.9
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Uncertain	2.7	M
PhyloP100	Pathogenic	8.1
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.94
Sift	Benign	0.040	D
Sift4G	Benign	0.074	T
Varity_R	N/A	0.87
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs77503355;

hg19: chr10-43609103;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar