rs75076352

chr10-43114500-T-Achr10-43114500-T-Cchr10-43114500-T-G

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.80

ACMG classification

Verdict is Pathogenic. Variant got 25 ACMG points.

• PS1: Transcript NM_020975 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 13910
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_020975
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 32.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43114501-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13911. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 10:43114500-T>A is Pathogenic according to our data. Variant chr10-43114500-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 38605. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43114500-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1900T>A	p.Cys634Ser	missense_variant	11/20	ENST00000355710.8
RET	NM_020630.6	c.1900T>A	p.Cys634Ser	missense_variant	11/19
RET	NM_001355216.1	c.1138T>A	p.Cys380Ser	missense_variant	8/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1900T>A	p.Cys634Ser	missense_variant	11/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2019

This sequence change replaces cysteine with serine at codon 634 of the RET protein (p.Cys634Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with medullary thyroid carcinoma (MTC) in several families (PMID: 15277225, 25143909, 21765987). It has also been observed in individuals affected with MTC and multiple endocrine neoplasia type 2 (MEN 2) (PMID: 28099363, 25440022, 9467562). ClinVar contains an entry for this variant (Variation ID: 38605). Experimental studies have shown that this missense change disrupts RET protein function (PMID: 29312610, 15277225). The p.Cys634 amino acid residue in RET has been determined to be clinically significant (PMID: 8103403, 27698838, 22900816, 23617071, 15472167, 21810974, 8570194, 7824936). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2016

The p.C634S pathogenic mutation (also known as c.1900T>A), located in coding exon 11 of the RET gene, results from a T to A substitution at nucleotide position 1900. The cysteine at codon 634 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in numerous families with multiple endocrine neoplasia type 2A (MEN2A) or familial medullary thyroid cancer (FMTC) and has been shown to segregate with disease in many of these families (Mulligan LM et al. Nat. Genet., 1994 Jan;6:70-4; Hedayati M et al. J Thyroid Res, 2011 Jun;2011:264248; Mahesh DM et al. Indian J Endocrinol Metab, 2014 Jul;18:516-20; Moore SW et al. J. Pediatr. Surg., 2007 Feb;42:326-32; Zhou Y et al. Clin. Endocrinol. (Oxf), 2007 Oct;67:570-6). This alteration has been shown by functional studies to lead to constitutive activation of RET tyrosine kinase and constitutive phosphorylation of MAPK (Melillo RM et al. Am. J. Pathol., 2004 Aug;165:511-21). This mutation occurs at a known hotspot and studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003; 138:409-16). Based on the available evidence, p.C634S is classified as a pathogenic mutation. Of note, the American Thyroid Association recommends that individuals with mutation in codon 634 begin surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid 2009 Jun;19(6):565-612). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.55

D

BayesDel_noAF

Pathogenic

0.55

Cadd

Pathogenic

28

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

D

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.73

D

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.7

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

T

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.99

MutPred

0.90

Loss of stability (P = 0.0466);.;Loss of stability (P = 0.0466);

MVP

0.97

MPC

0.72

ClinPred

1.0

D

GERP RS

4.5

Varity_R

0.70

gMVP

0.94

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75076352; hg19: chr10-43609948; COSMIC: COSV60686416;