10-43119548-G-C

Variant names:

• chr10-43119548-G-C
• rs79658334
• NM_020975.6:c.2410G>C

Variant summary

Our verdict is Pathogenic. The variant received 28 ACMG points: 28P and 0B. PS1_Very_Strong PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.2410G>C​(p.Val804Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,366 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: "SCV004839086: Functional studies have reported that this variant resulted in intermediate level of transforming activity on ex vivo transfected cells (PMID:9242375, 10445857) and to confer resistance to select kinase inhibitors (PMID:26046350)." 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. V804A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.99
• Publications: 467 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 28 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: SCV004839086: Functional studies have reported that this variant resulted in intermediate level of transforming activity on ex vivo transfected cells (PMID: 9242375, 10445857) and to confer resistance to select kinase inhibitors (PMID: 26046350).; SCV004930973: Functional studies indicate this variant impacts protein function [PMID: 9242375].; SCV000565490: Published functional studies demonstrate a damaging effect: increased transforming activity and autophosphorylation ability (Carlomagno et al., 2004; Iwashita et al., 1999; Pasini et al., 1997);; SCV002736148: Functional studies demonstrate that p.V804L transfected cells exhibit an increase in the level of tyrosine phosphorylation compared to wildtype in one RET isoform, supporting its oncogenic potential (Pasini A et al. Oncogene 1997 Jul;15(4):393-402).; SCV005902150: Functional assays have demonstrated that RET Val804Leu induces autophosphorylation of tyrosine residues and transformation activity in fibroblasts, although with a transforming capacity lower than high risk variants C634R and M918T (PMID: 9242375, PMID:10445857)(PS3_Supporting).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43119548-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 10-43119548-G-C is Pathogenic according to our data. Variant chr10-43119548-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38613.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.2410G>C	p.Val804Leu	missense	Exon 14 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.2410G>C	p.Val804Leu	missense	Exon 14 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.2410G>C	p.Val804Leu	missense	Exon 14 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.2410G>C	p.Val804Leu	missense	Exon 14 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.2410G>C	p.Val804Leu	missense	Exon 14 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.2146G>C	p.Val716Leu	missense	Exon 14 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453366 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 722824

African (AFR) AF: 0.00 AC: 0 AN: 33274

American (AMR) AF: 0.00 AC: 0 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39396

South Asian (SAS) AF: 0.00 AC: 0 AN: 85494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4770

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109962

Other (OTH) AF: 0.00 AC: 0 AN: 60004

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Multiple endocrine neoplasia, type 2 (3)
3	-	-	not provided (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	MEN2 phenotype: Unclassified (1)
1	-	-	Multiple endocrine neoplasia type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	-0.33	N
PhyloP100		10
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.72
Sift	Benign	0.031	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.90		Loss of methylation at K808 (P = 0.1007)
MVP		0.92
MPC		0.77
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.85
gMVP		0.76
Mutation Taster		=1/99	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: rs79658334; hg19: chr10-43614996;