NM_000051.4(ATM):c.6824T>C (p.Ile2275Thr) AND Ataxia-telangiectasia syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 21, 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:: RCV001036032.14

Allele description [Variation Report for NM_000051.4(ATM):c.6824T>C (p.Ile2275Thr)]

NM_000051.4(ATM):c.6824T>C (p.Ile2275Thr)

Genes:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.6824T>C (p.Ile2275Thr)

HGVS:

NC_000011.10:g.108326074T>C
NG_009830.1:g.108243T>C
NG_054724.1:g.148759A>G
NM_000051.4:c.6824T>CMANE SELECT
NM_001330368.2:c.641-17003A>G
NM_001351110.2:c.*38+9146A>G
NM_001351834.2:c.6824T>C
NP_000042.3:p.Ile2275Thr
NP_000042.3:p.Ile2275Thr
NP_001338763.1:p.Ile2275Thr
LRG_135t1:c.6824T>C
LRG_135:g.108243T>C
LRG_135p1:p.Ile2275Thr
NC_000011.9:g.108196801T>C
NM_000051.3:c.6824T>C

Protein change:

I2275T

Links:

dbSNP: rs1283858462

NCBI 1000 Genomes Browser:

rs1283858462

Molecular consequence:

NM_001330368.2:c.641-17003A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+9146A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6824T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6824T>C - 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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gi|49494924|gnl|dbEST|23937830|gb|C 33.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001199375	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 21, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33436325, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001199375

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 21, 2022)

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	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

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001199375.4

#	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 isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2275 of the ATM protein (p.Ile2275Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with prostate cancer (PMID: 33436325). ClinVar contains an entry for this variant (Variation ID: 631410). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM 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

Last Updated: Oct 20, 2024

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