NM_020975.6(RET):c.1201A>T (p.Ser401Cys) AND Multiple endocrine neoplasia, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000560396.13

Allele description [Variation Report for NM_020975.6(RET):c.1201A>T (p.Ser401Cys)]

NM_020975.6(RET):c.1201A>T (p.Ser401Cys)

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.1201A>T (p.Ser401Cys)

HGVS:

NC_000010.11:g.43109168A>T
NG_007489.1:g.37100A>T
NM_000323.2:c.1201A>T
NM_001355216.2:c.439A>T
NM_001406743.1:c.1201A>T
NM_001406744.1:c.1201A>T
NM_001406759.1:c.1201A>T
NM_001406760.1:c.1201A>T
NM_001406761.1:c.1072A>T
NM_001406762.1:c.1072A>T
NM_001406763.1:c.1201A>T
NM_001406764.1:c.1072A>T
NM_001406765.1:c.1201A>T
NM_001406766.1:c.913A>T
NM_001406767.1:c.913A>T
NM_001406768.1:c.1072A>T
NM_001406770.1:c.913A>T
NM_001406771.1:c.763A>T
NM_001406773.1:c.763A>T
NM_001406775.1:c.475A>T
NM_001406776.1:c.475A>T
NM_001406777.1:c.475A>T
NM_001406778.1:c.475A>T
NM_001406784.1:c.211A>T
NM_020629.2:c.1201A>T
NM_020630.7:c.1201A>T
NM_020975.6:c.1201A>TMANE SELECT
NP_000314.1:p.Ser401Cys
NP_001342145.1:p.Ser147Cys
NP_001342145.1:p.Ser147Cys
NP_001393672.1:p.Ser401Cys
NP_001393673.1:p.Ser401Cys
NP_001393688.1:p.Ser401Cys
NP_001393689.1:p.Ser401Cys
NP_001393690.1:p.Ser358Cys
NP_001393691.1:p.Ser358Cys
NP_001393692.1:p.Ser401Cys
NP_001393693.1:p.Ser358Cys
NP_001393694.1:p.Ser401Cys
NP_001393695.1:p.Ser305Cys
NP_001393696.1:p.Ser305Cys
NP_001393697.1:p.Ser358Cys
NP_001393699.1:p.Ser305Cys
NP_001393700.1:p.Ser255Cys
NP_001393702.1:p.Ser255Cys
NP_001393704.1:p.Ser159Cys
NP_001393705.1:p.Ser159Cys
NP_001393706.1:p.Ser159Cys
NP_001393707.1:p.Ser159Cys
NP_001393713.1:p.Ser71Cys
NP_065680.1:p.Ser401Cys
NP_065681.1:p.Ser401Cys
NP_065681.1:p.Ser401Cys
NP_065681.1:p.Ser401Cys
NP_066124.1:p.Ser401Cys
NP_066124.1:p.Ser401Cys
LRG_518t1:c.1201A>T
LRG_518t2:c.1201A>T
LRG_518:g.37100A>T
LRG_518p1:p.Ser401Cys
LRG_518p2:p.Ser401Cys
NC_000010.10:g.43604616A>T
NM_001355216.1:c.439A>T
NM_020630.4:c.1201A>T
NM_020630.6:c.1201A>T
NM_020975.4:c.1201A>T

Protein change:

S147C

Links:

dbSNP: rs140638866

NCBI 1000 Genomes Browser:

rs140638866

Molecular consequence:

NM_000323.2:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.439A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.1072A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.1072A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.1072A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.913A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.913A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.1072A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.913A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.763A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.763A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.475A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.475A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.475A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.475A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.211A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.1201A>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Multiple endocrine neoplasia, type 2 (MEN2)
Identifiers:: MONDO: MONDO:0019003; MedGen: C4048306

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000658396	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 4, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27657687, 28492532
SCV004822634	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 3, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27657687, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000658396

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 4, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004822634

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 3, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	15	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.

Bekheirnia MR, Bekheirnia N, Bainbridge MN, Gu S, Coban Akdemir ZH, Gambin T, Janzen NK, Jhangiani SN, Muzny DM, Michael M, Brewer ED, Elenberg E, Kale AS, Riley AA, Swartz SJ, Scott DA, Yang Y, Srivaths PR, Wenderfer SE, Bodurtha J, Applegate CD, Velinov M, et al.

Genet Med. 2017 Apr;19(4):412-420. doi: 10.1038/gim.2016.131. Epub 2016 Sep 22.

PubMed [citation]

PMID:: 27657687
PMCID:: PMC5362362

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000658396.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 401 of the RET protein (p.Ser401Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital anomalies of the kidney and urinary tract (PMID: 27657687). ClinVar contains an entry for this variant (Variation ID: 224354). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 All of Us Research Program, National Institutes of Health, SCV004822634.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	15	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces serine with cysteine at codon 401 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital anomalies of the kidney and urinary tract (PMID: 27657687). This variant has been identified in 11/282496 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		15	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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