NM_000051.4(ATM):c.6554T>C (p.Ile2185Thr) AND Ataxia-telangiectasia syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 28, 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:: RCV000686103.19

Allele description [Variation Report for NM_000051.4(ATM):c.6554T>C (p.Ile2185Thr)]

NM_000051.4(ATM):c.6554T>C (p.Ile2185Thr)

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.6554T>C (p.Ile2185Thr)

HGVS:

NC_000011.10:g.108321402T>C
NG_009830.1:g.103571T>C
NG_054724.1:g.153431A>G
NM_000051.4:c.6554T>CMANE SELECT
NM_001330368.2:c.641-12331A>G
NM_001351110.2:c.*39-12331A>G
NM_001351834.2:c.6554T>C
NP_000042.3:p.Ile2185Thr
NP_000042.3:p.Ile2185Thr
NP_001338763.1:p.Ile2185Thr
LRG_135t1:c.6554T>C
LRG_135:g.103571T>C
LRG_135p1:p.Ile2185Thr
NC_000011.9:g.108192129T>C
NM_000051.3:c.6554T>C

Protein change:

I2185T

Links:

dbSNP: rs779611511

NCBI 1000 Genomes Browser:

rs779611511

Molecular consequence:

NM_001330368.2:c.641-12331A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-12331A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6554T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6554T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000813606	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 28779002, 33608381, 35171259, 35264596, 28492532
SCV000838577	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV001458450	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

SCV000813606

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 28, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000838577

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(Jul 2, 2018)

unknown

clinical testing

Citation Link,

SCV001458450

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.

Decker B, Allen J, Luccarini C, Pooley KA, Shah M, Bolla MK, Wang Q, Ahmed S, Baynes C, Conroy DM, Brown J, Luben R, Ostrander EA, Pharoah PD, Dunning AM, Easton DF.

J Med Genet. 2017 Nov;54(11):732-741. doi: 10.1136/jmedgenet-2017-104588. Epub 2017 Aug 4.

PubMed [citation]

PMID:: 28779002
PMCID:: PMC5740532

Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance.

Pandya D, Shah M, Kaplan F, Martino C, Levy G, Kazanjian M, Batter S, Martignetti J, Frank RC.

Cold Spring Harb Mol Case Stud. 2021 Feb 19;7(1). doi:pii: a005801. 10.1101/mcs.a005801. Print 2021 Feb.

PubMed [citation]

PMID:: 33608381
PMCID:: PMC7903888

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000813606.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2185 of the ATM protein (p.Ile2185Thr). This variant is present in population databases (rs779611511, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, and/or prostate cancer (PMID: 28779002, 33608381, 35171259, 35264596). ClinVar contains an entry for this variant (Variation ID: 246421). 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 Mendelics, SCV000838577.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001458450.1

#	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: Oct 26, 2024

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