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NM_000051.4(ATM):c.8246A>T (p.Lys2749Ile) AND Ataxia-telangiectasia syndrome

Germline classification:
Uncertain significance (4 submissions)
Last evaluated:
Oct 28, 2022
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:
RCV000347894.23

Allele description [Variation Report for NM_000051.4(ATM):c.8246A>T (p.Lys2749Ile)]

NM_000051.4(ATM):c.8246A>T (p.Lys2749Ile)

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.8246A>T (p.Lys2749Ile)
HGVS:
  • NC_000011.10:g.108335939A>T
  • NG_009830.1:g.118108A>T
  • NG_054724.1:g.138894T>A
  • NM_000051.4:c.8246A>TMANE SELECT
  • NM_001330368.2:c.641-26868T>A
  • NM_001351110.2:c.695-647T>A
  • NM_001351834.2:c.8246A>T
  • NP_000042.3:p.Lys2749Ile
  • NP_000042.3:p.Lys2749Ile
  • NP_001338763.1:p.Lys2749Ile
  • LRG_135t1:c.8246A>T
  • LRG_135:g.118108A>T
  • LRG_135p1:p.Lys2749Ile
  • NC_000011.9:g.108206666A>T
  • NM_000051.3:c.8246A>T
Protein change:
K2749I
Links:
dbSNP: rs779145081
NCBI 1000 Genomes Browser:
rs779145081
Molecular consequence:
  • NM_001330368.2:c.641-26868T>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001351110.2:c.695-647T>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000051.4:c.8246A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.8246A>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000367068Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV000547049Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Oct 28, 2022)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000838610Mendelics
criteria provided, single submitter

(Mendelics Assertion Criteria 2017)
Uncertain significance
(Jul 2, 2018)
unknownclinical testing

Citation Link,

SCV001462606Natera, Inc.
no assertion criteria provided
Uncertain significance
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinicopathologic Features and Germline Sequence Variants in Young Patients (≤40 Years Old) With Pancreatic Ductal Adenocarcinoma.

Ohmoto A, Yachida S, Kubo E, Takai E, Suzuki M, Shimada K, Okusaka T, Morizane C.

Pancreas. 2016 Aug;45(7):1056-61. doi: 10.1097/MPA.0000000000000574.

PubMed [citation]
PMID:
26692440

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]
PMID:
30287823
PMCID:
PMC6172276
See all PubMed Citations (4)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000367068.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000547049.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2749 of the ATM protein (p.Lys2749Ile). This variant is present in population databases (rs779145081, gnomAD 0.04%). This missense change has been observed in individual(s) with pancreatic cancer and breast cancer, as well as in unaffected controls (PMID: 26692440, 30287823, 30851086). ClinVar contains an entry for this variant (Variation ID: 230416). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV000838610.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001462606.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 8, 2025