NM_000051.4(ATM):c.4673C>T (p.Thr1558Met) AND Ataxia-telangiectasia syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 4, 2024
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:: RCV000542530.9

Allele description [Variation Report for NM_000051.4(ATM):c.4673C>T (p.Thr1558Met)]

NM_000051.4(ATM):c.4673C>T (p.Thr1558Met)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.4673C>T (p.Thr1558Met)

Other names:

p.T1558M:ACG>ATG

HGVS:

NC_000011.10:g.108293374C>T
NG_009830.1:g.75543C>T
NM_000051.4:c.4673C>TMANE SELECT
NM_001351834.2:c.4673C>T
NP_000042.3:p.Thr1558Met
NP_000042.3:p.Thr1558Met
NP_001338763.1:p.Thr1558Met
LRG_135t1:c.4673C>T
LRG_135:g.75543C>T
LRG_135p1:p.Thr1558Met
NC_000011.9:g.108164101C>T
NM_000051.3:c.4673C>T
p.T1558M

Protein change:

T1558M

Links:

dbSNP: rs587781712

NCBI 1000 Genomes Browser:

rs587781712

Molecular consequence:

NM_000051.4:c.4673C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.4673C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Ataxia-telangiectasia syndrome (AT)
Synonyms:: Louis-Bar syndrome; Cerebello-oculocutaneous telangiectasia; Immunodeficiency with ataxia telangiectasia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008840; MedGen: C0004135; Orphanet: 100; OMIM: 208900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000622522	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 4, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 33436325, 34326862, 28492532
SCV001462336	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000622522

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 4, 2024)

germline

clinical testing

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

SCV001462336

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

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

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

Karlsson Q, Brook MN, Dadaev T, Wakerell S, Saunders EJ, Muir K, Neal DE, Giles GG, MacInnis RJ, Thibodeau SN, McDonnell SK, Cannon-Albright L, Teixeira MR, Paulo P, Cardoso M, Huff C, Li D, Yao Y, Scheet P, Permuth JB, Stanford JL, Dai JY, et al.

Eur Urol Oncol. 2021 Aug;4(4):570-579. doi: 10.1016/j.euo.2020.12.001. Epub 2021 Jan 9.

PubMed [citation]

PMID:: 33436325
PMCID:: PMC8381233

Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.

Bhai P, Levy MA, Rooney K, Carere DA, Reilly J, Kerkhof J, Volodarsky M, Stuart A, Kadour M, Panabaker K, Schenkel LC, Lin H, Ainsworth P, Sadikovic B.

Front Genet. 2021;12:698595. doi: 10.3389/fgene.2021.698595.

PubMed [citation]

PMID:: 34326862
PMCID:: PMC8314385

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000622522.7

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1558 of the ATM protein (p.Thr1558Met). This variant is present in population databases (rs587781712, gnomAD 0.02%). This missense change has been observed in individual(s) with gastric cancer and/or prostate cancer (PMID: 33436325, 34326862). ClinVar contains an entry for this variant (Variation ID: 141389). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 Natera, Inc., SCV001462336.1

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

#	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: Mar 16, 2024

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