NM_020975.6(RET):c.2410G>A (p.Val804Met) AND RET-related disorder

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Oct 4, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004528141.3

Allele description [Variation Report for NM_020975.6(RET):c.2410G>A (p.Val804Met)]

NM_020975.6(RET):c.2410G>A (p.Val804Met)

Gene:

RET:ret proto-oncogene [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q11.21

Genomic location:

Preferred name:

NM_020975.6(RET):c.2410G>A (p.Val804Met)

HGVS:

NC_000010.11:g.43119548G>A
NG_007489.1:g.47480G>A
NM_000323.2:c.2410G>A
NM_001355216.2:c.1648G>A
NM_001406743.1:c.2410G>A
NM_001406744.1:c.2410G>A
NM_001406759.1:c.2410G>A
NM_001406760.1:c.2410G>A
NM_001406761.1:c.2281G>A
NM_001406762.1:c.2281G>A
NM_001406763.1:c.2275G>A
NM_001406764.1:c.2281G>A
NM_001406765.1:c.2275G>A
NM_001406766.1:c.2122G>A
NM_001406767.1:c.2122G>A
NM_001406768.1:c.2146G>A
NM_001406769.1:c.2014G>A
NM_001406770.1:c.2122G>A
NM_001406771.1:c.1972G>A
NM_001406772.1:c.2014G>A
NM_001406773.1:c.1972G>A
NM_001406774.1:c.1885G>A
NM_001406775.1:c.1684G>A
NM_001406776.1:c.1684G>A
NM_001406777.1:c.1684G>A
NM_001406778.1:c.1684G>A
NM_001406779.1:c.1513G>A
NM_001406780.1:c.1513G>A
NM_001406781.1:c.1513G>A
NM_001406782.1:c.1513G>A
NM_001406783.1:c.1384G>A
NM_001406784.1:c.1420G>A
NM_001406785.1:c.1393G>A
NM_001406786.1:c.1384G>A
NM_001406787.1:c.1378G>A
NM_001406788.1:c.1225G>A
NM_001406789.1:c.1225G>A
NM_001406790.1:c.1225G>A
NM_001406791.1:c.1105G>A
NM_001406792.1:c.961G>A
NM_001406793.1:c.961G>A
NM_001406794.1:c.961G>A
NM_020629.2:c.2410G>A
NM_020630.7:c.2410G>A
NM_020975.6:c.2410G>AMANE SELECT
NP_000314.1:p.Val804Met
NP_001342145.1:p.Val550Met
NP_001342145.1:p.Val550Met
NP_001393672.1:p.Val804Met
NP_001393673.1:p.Val804Met
NP_001393688.1:p.Val804Met
NP_001393689.1:p.Val804Met
NP_001393690.1:p.Val761Met
NP_001393691.1:p.Val761Met
NP_001393692.1:p.Val759Met
NP_001393693.1:p.Val761Met
NP_001393694.1:p.Val759Met
NP_001393695.1:p.Val708Met
NP_001393696.1:p.Val708Met
NP_001393697.1:p.Val716Met
NP_001393698.1:p.Val672Met
NP_001393699.1:p.Val708Met
NP_001393700.1:p.Val658Met
NP_001393701.1:p.Val672Met
NP_001393702.1:p.Val658Met
NP_001393703.1:p.Val629Met
NP_001393704.1:p.Val562Met
NP_001393705.1:p.Val562Met
NP_001393706.1:p.Val562Met
NP_001393707.1:p.Val562Met
NP_001393708.1:p.Val505Met
NP_001393709.1:p.Val505Met
NP_001393710.1:p.Val505Met
NP_001393711.1:p.Val505Met
NP_001393712.1:p.Val462Met
NP_001393713.1:p.Val474Met
NP_001393714.1:p.Val465Met
NP_001393715.1:p.Val462Met
NP_001393716.1:p.Val460Met
NP_001393717.1:p.Val409Met
NP_001393718.1:p.Val409Met
NP_001393719.1:p.Val409Met
NP_001393720.1:p.Val369Met
NP_001393721.1:p.Val321Met
NP_001393722.1:p.Val321Met
NP_001393723.1:p.Val321Met
NP_065680.1:p.Val804Met
NP_065681.1:p.Val804Met
NP_065681.1:p.Val804Met
NP_065681.1:p.Val804Met
NP_066124.1:p.Val804Met
NP_066124.1:p.Val804Met
LRG_518t1:c.2410G>A
LRG_518t2:c.2410G>A
LRG_518:g.47480G>A
LRG_518p1:p.Val804Met
LRG_518p2:p.Val804Met
NC_000010.10:g.43614996G>A
NM_001355216.1:c.1648G>A
NM_020630.4:c.2410G>A
NM_020630.6:c.2410G>A
NM_020975.4:c.2410G>A
NM_020975.5:c.2410G>A
P07949:p.Val804Met

Protein change:

V321M; VAL804MET

Links:

UniProtKB: P07949#VAR_006337; OMIM: 164761.0043; dbSNP: rs79658334

NCBI 1000 Genomes Browser:

rs79658334

Molecular consequence:

NM_000323.2:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1648G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.2275G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.2275G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.2146G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.2014G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1972G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.2014G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1972G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1885G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.1384G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.1393G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.1384G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.1105G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RET-related disorder
Synonyms:: RET-related disorders; RET-related condition; RET-related disease
Identifiers:

Recent activity

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gamma-sarcoglycan isoform X1 [Daktulosphaira vitifoliae]
gamma-sarcoglycan isoform X1 [Daktulosphaira vitifoliae]
gi|2304382728|ref|XP_050527328.1|

Protein
MULTISPECIES: thiazole biosynthesis adenylyltransferase ThiF [Enterobacter]
MULTISPECIES: thiazole biosynthesis adenylyltransferase ThiF [Enterobacter]
gi|695625786|ref|WP_032608234.1|

Protein
MULTISPECIES: uroporphyrinogen decarboxylase [Enterobacter]
MULTISPECIES: uroporphyrinogen decarboxylase [Enterobacter]
gi|550794718|ref|WP_022650209.1|

Protein
dnaJ homolog subfamily B member 3-like isoform X2 [Argiope bruennichi]
dnaJ homolog subfamily B member 3-like isoform X2 [Argiope bruennichi]
gi|2504415520|ref|XP_055939109.1|

Protein
PREDICTED: Mus musculus NCK-associated protein 5 (Nckap5), transcript variant X1...
PREDICTED: Mus musculus NCK-associated protein 5 (Nckap5), transcript variant X19, mRNA
gi|1907068037|ref|XM_036163207.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000807027	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Aug 2, 2024)	germline	clinical testing
SCV004183391	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000807027

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Aug 2, 2024)

germline

clinical testing

SCV004183391

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 4, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV000807027.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The RET c.2410G>A variant is predicted to result in the amino acid substitution p.Val804Met. This variant has been reported in individuals with medullary thyroid carcinoma (reported as c804 in Frohnauer and Decker. 2000. PubMed ID:11114642; Choi et al. 2013. PubMed ID: 23341727; Kasprzak et al. 2001. PubMed ID: 11732489; Rothberg et al. 2009. PubMed ID: 19445625). However, some reports have described this variant as having low penetrance and only causing carcinoma in the homozygous state (Lecube et al. 2002. PubMed ID 12019403; Lesueur et al. 2005. PubMed ID 15741265). Functional studies show the p.Val804Met variant results in slightly higher growth and transformation rates compared to wild type RET (Cosci et al. 2011. PubMed ID: 21810974). Notably, an alternate substitution of this amino acid (p.Val804Leu) has also been reported in individuals with thyroid cancer (Kruckeberg and Thibodeau. 2004. PubMed ID 14718397; Table S1 in Currás-Freixes et al. 2015. PubMed ID 26269449; Pasini et al. 1997. PubMed ID 9242375). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. This variant is classified as pathogenic/likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37102/). Based on the available information, this variant is interpreted as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV004183391.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PS3 supporting, PM5 moderated, PM6 moderated, PP3 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

ClinVar

Relating variation to medicine