NM_017849.4(TMEM127):c.464T>A (p.Leu155Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 30, 2023
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:: RCV000564643.6

Allele description [Variation Report for NM_017849.4(TMEM127):c.464T>A (p.Leu155Ter)]

NM_017849.4(TMEM127):c.464T>A (p.Leu155Ter)

Gene:

TMEM127:transmembrane protein 127 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q11.2

Genomic location:

Preferred name:

NM_017849.4(TMEM127):c.464T>A (p.Leu155Ter)

HGVS:

NC_000002.12:g.96254061A>T
NG_027695.1:g.16953T>A
NM_001193304.3:c.464T>A
NM_017849.4:c.464T>AMANE SELECT
NP_001180233.1:p.Leu155Ter
NP_060319.1:p.Leu155Ter
NP_060319.1:p.Leu155Ter
LRG_528t1:c.464T>A
LRG_528:g.16953T>A
LRG_528p1:p.Leu155Ter
NC_000002.11:g.96919799A>T
NM_017849.3:c.464T>A

Protein change:

L155*

Links:

dbSNP: rs886039439

NCBI 1000 Genomes Browser:

rs886039439

Molecular consequence:

NM_001193304.3:c.464T>A - nonsense - [Sequence Ontology: SO:0001587]
NM_017849.4:c.464T>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000675310	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 30, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002527256	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Dec 11, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 26960314, 29625052, 30113886 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000675310

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jun 30, 2023)

germline

clinical testing

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

Citation Link,

SCV002527256

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Dec 11, 2021)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

Novel SDHB and TMEM127 Mutations in Patients with Pheochromocytoma/Paraganglioma Syndrome.

Patócs A, Lendvai NK, Butz H, Liko I, Sapi Z, Szucs N, Toth G, Grolmusz VK, Igaz P, Toth M, Rácz K.

Pathol Oncol Res. 2016 Oct;22(4):673-9. doi: 10.1007/s12253-016-0050-0. Epub 2016 Mar 9.

PubMed [citation]

PMID:: 26960314

Pathogenic Germline Variants in 10,389 Adult Cancers.

Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, Paczkowska M, Reynolds S, Wyczalkowski MA, Oak N, Scott AD, Krassowski M, Cherniack AD, Houlahan KE, Jayasinghe R, Wang LB, Zhou DC, Liu D, Cao S, Kim YW, Koire A, McMichael JF, et al.

Cell. 2018 Apr 5;173(2):355-370.e14. doi: 10.1016/j.cell.2018.03.039.

PubMed [citation]

PMID:: 29625052
PMCID:: PMC5949147

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000675310.6

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

Description

The p.L155* variant (also known as c.464T>A), located in coding exon 3 of the TMEM127 gene, results from a T to A substitution at nucleotide position 464. This changes the amino acid from a leucine to a stop codon within coding exon 3. This alteration occurs at the 3' terminus of theTMEM127 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 84 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported as a disease-causing mutation in a 51 year old patient with bilateral pheochromocytoma and intra-abdominal and head/neck paraganglioma (Patócs A et al. Pathol. Oncol. Res., 2016 Oct;22:673-9). Based on the majority of available evidence to date, this variant is likely to be 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 Sema4, Sema4, SCV002527256.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	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: Sep 29, 2024

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