chr10-43114502-C-G

Variant names:

• chr10-43114502-C-G
• rs77709286
• NM_020975.6:c.1902C>G
• RET p.Cys634Trp

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). PS3PM1PM2PM5PP3_ModeratePP5_Strong

The NM_020975.6(RET):c.1902C>G (p.Cys634Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004930963: Functional studies indicate this variant impacts protein function [PMID:9230192, 34905813]." 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.C634S: Pathogenic (ClinVar VariationId 1782209, 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)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.92
• Publications: 194 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV004930963: Functional studies indicate this variant impacts protein function [PMID: 9230192, 34905813].; SCV000329489: Published functional studies demonstrate a damaging effect: high transforming efficiency and clonogenic ability, constitutive activation of RET protein (Santoro 1995); SCV000886051: Further, functional studies demonstrate that this variant causes the RET protein to be constitutively activated (Santoro 1995).; SCV000543831: Experimental studies have shown that this missense change affects RET function (PMID: 7824936).
	PM1Mutational hot spot or critical domain		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).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000122 by highest known P/LP ClinVar AF 0.000122) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		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.C634S: Pathogenic (ClinVar VariationId 1782209, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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.1902C>G p.Cys634Trp	missense	Exon 11 of 20	Prot: NP_066124.1 UniProt:
	RET NM_001406743.1		c.1902C>G p.Cys634Trp	missense	Exon 11 of 21	Prot: NP_001393672.1 UniProt:
	RET NM_001406744.1		c.1902C>G p.Cys634Trp	missense	Exon 11 of 20	Prot: NP_001393673.1

RET NM_020975.6

MANE Select

HGVSc / HGVSpc.1902C>Gp.Cys634Trp

Exon rankExon 11 of 20

missense

Prot: NP_066124.1UniProt: P07949-1

RET NM_001406743.1

HGVSc / HGVSpc.1902C>Gp.Cys634Trp

Exon rankExon 11 of 21

missense

Prot: NP_001393672.1UniProt: P07949-1

RET NM_001406744.1

HGVSc / HGVSpc.1902C>Gp.Cys634Trp

Exon rankExon 11 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.1902C>G p.Cys634Trp	missense	Exon 11 of 20	Prot: ENSP00000347942.3 UniProt:
	RET ENST00000340058.6	TSL:1	c.1902C>G p.Cys634Trp	missense	Exon 11 of 19	Prot: ENSP00000344798.4 UniProt:
	RET ENST00000615310.5	TSL:5	c.1506C>G p.Cys502Trp	missense	Exon 9 of 17	Prot: ENSP00000480088.2 UniProt:

RET ENST00000355710.8

TSL:5MANE Select

HGVSc / HGVSpc.1902C>Gp.Cys634Trp

Exon rankExon 11 of 20

missense

Prot: ENSP00000347942.3UniProt: P07949-1

RET ENST00000340058.6

TSL:1

HGVSc / HGVSpc.1902C>Gp.Cys634Trp

Exon rankExon 11 of 19

missense

Prot: ENSP00000344798.4UniProt: P07949-2

RET ENST00000615310.5

TSL:5

HGVSc / HGVSpc.1506C>Gp.Cys502Trp

Exon rankExon 9 of 17

missense

Prot: ENSP00000480088.2UniProt: A0A087WWB1

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000404	AC:1	Hom:	AN:247602	Cov:
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

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 2A (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Multiple endocrine neoplasia, type 2 (1)
1	-	-	Pheochromocytoma (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.87	D
GPN-Star LLR	N/A	-7.8
GPN-Star score	N/A	7.8
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.87	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	Benign	1.9
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.94
VESM-3B	Benign	-12

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
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: rs77709286;

hg19: chr10-43609950;

COSMIC: COSV60687444;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar