10-43120184-C-T

Variant names:

• chr10-43120184-C-T
• rs267607011
• NM_020975.6:c.2711C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_020975.6(RET):​c.2711C>T​(p.Ser904Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,846 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S904A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.03
• Publications: 58 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 10-43120184-C-T is Pathogenic according to our data. Variant chr10-43120184-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 24963.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.2711C>T	p.Ser904Phe	missense_variant	Exon 15 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2711C>T	p.Ser904Phe	missense_variant	Exon 15 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460846 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726724

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111964

Other (OTH) AF: 0.0000166 AC: 1 AN: 60304

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia type 2A Pathogenic:1

Nov 20, 2020

Division of Medical Genetics, Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser904Phe variant, previously reported in one family with father and son affected by adult-onset MTC and hypothesized as belonging to the lowest risk level based on results of in silico and in vitro analyses (Cosci et al 2011, Elisei et al 2019), was identified in ten individuals from a single family, seven of whom affected by adult-onset MTC. Thus, the availability of several genetically and clinically characterized members allowed to provide evidence that the p.Ser904Phe variant is highly penetrant but leads to the development of slowly-progressing MTC at relatively advanced age. -

not provided Pathogenic:1

Jun 18, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.2711C>T;p.Ser904Phe variant has been published in at least one family with medullary thyroid carcinoma (Cosci 2011, Elisei 2007). The variant has also been shown to perform similarly to known pathogenic variants in at least one in vitro study (Cosci 2011). Additionally, this variant is located in the tyrosine kinase domain, immediately adjacent to tyrosine 905, which is critical in several of the protein's functions (Arighi 2005). The variant is described in the ClinVar database (Variation ID: 24963) and the dbSNP variant database (rs267607011), but not in the general population abased databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is highly conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Arighi E et al. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005 Aug-Oct;16(4-5):441-67. Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011 Sep 20;18(5):603-12. Elisei R et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007 Dec;92(12):4725-9. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S904F variant (also known as c.2711C>T), located in coding exon 15 of the RET gene, results from a C to T substitution at nucleotide position 2711. The serine at codon 904 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with multiple endocrine neoplasia type 2 (MEN2) (Innella G et al. Cancers (Basel), 2020 Nov;12). In an assay testing RET function, this variant showed a functionally abnormal result (Nakaoku T et al. Nat Commun, 2018 Feb;9:625). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.57	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.6	L;L
PhyloP100		5.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.083	T;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.62		Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);
MVP		0.95
MPC		0.51
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.94
Mutation Taster		=12/88	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: rs267607011; hg19: chr10-43615632;