10-43114502-C-A

Variant names:

• chr10-43114502-C-A
• rs77709286
• NM_020975.6:c.1902C>A
• RET p.Cys634*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2

The NM_020975.6(RET):c.1902C>A (p.Cys634*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The variant position is a cancer hotspot (cancerhotspots.org) with 45 samples affected at this amino acid position.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 2 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 10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 11 of 20) at amino acid 634 of 1114, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	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.

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>A p.Cys634*	stop_gained	Exon 11 of 20	Prot: NP_066124.1 UniProt:
	RET NM_001406743.1		c.1902C>A p.Cys634*	stop_gained	Exon 11 of 21	Prot: NP_001393672.1 UniProt:
	RET NM_001406744.1		c.1902C>A p.Cys634*	stop_gained	Exon 11 of 20	Prot: NP_001393673.1

RET NM_020975.6

MANE Select

HGVSc / HGVSpc.1902C>Ap.Cys634*

Exon rankExon 11 of 20

stop_gained

Prot: NP_066124.1UniProt: P07949-1

RET NM_001406743.1

HGVSc / HGVSpc.1902C>Ap.Cys634*

Exon rankExon 11 of 21

stop_gained

Prot: NP_001393672.1UniProt: P07949-1

RET NM_001406744.1

HGVSc / HGVSpc.1902C>Ap.Cys634*

Exon rankExon 11 of 20

stop_gained

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>A p.Cys634*	stop_gained	Exon 11 of 20	Prot: ENSP00000347942.3 UniProt:
	RET ENST00000340058.6	TSL:1	c.1902C>A p.Cys634*	stop_gained	Exon 11 of 19	Prot: ENSP00000344798.4 UniProt:
	RET ENST00000615310.5	TSL:5	c.1506C>A p.Cys502*	stop_gained	Exon 9 of 17	Prot: ENSP00000480088.2 UniProt:

RET ENST00000355710.8

TSL:5MANE Select

HGVSc / HGVSpc.1902C>Ap.Cys634*

Exon rankExon 11 of 20

stop_gained

Prot: ENSP00000347942.3UniProt: P07949-1

RET ENST00000340058.6

TSL:1

HGVSc / HGVSpc.1902C>Ap.Cys634*

Exon rankExon 11 of 19

stop_gained

Prot: ENSP00000344798.4UniProt: P07949-2

RET ENST00000615310.5

TSL:5

HGVSc / HGVSpc.1506C>Ap.Cys502*

Exon rankExon 9 of 17

stop_gained

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	35
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.86	D
GPN-Star LLR	N/A	-8.4
GPN-Star score	N/A	8.4
Mutation Taster	N/A	0/200	disease causing (fs/PTC)
PhyloP100	Benign	1.9

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar