NM_000051.4(ATM):c.7181C>T (p.Ser2394Leu) AND Ataxia-telangiectasia syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Mar 22, 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:: RCV000534806.22

Allele description [Variation Report for NM_000051.4(ATM):c.7181C>T (p.Ser2394Leu)]

NM_000051.4(ATM):c.7181C>T (p.Ser2394Leu)

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.7181C>T (p.Ser2394Leu)

Other names:

p.S2394L:TCA>TTA

HGVS:

NC_000011.10:g.108329112C>T
NG_009830.1:g.111281C>T
NG_054724.1:g.145721G>A
NM_000051.4:c.7181C>TMANE SELECT
NM_001330368.2:c.641-20041G>A
NM_001351110.2:c.*38+6108G>A
NM_001351834.2:c.7181C>T
NP_000042.3:p.Ser2394Leu
NP_000042.3:p.Ser2394Leu
NP_001338763.1:p.Ser2394Leu
LRG_135t1:c.7181C>T
LRG_135:g.111281C>T
LRG_135p1:p.Ser2394Leu
NC_000011.9:g.108199839C>T
NM_000051.3:c.7181C>T

Protein change:

S2394L

Links:

dbSNP: rs587779861

NCBI 1000 Genomes Browser:

rs587779861

Molecular consequence:

NM_001330368.2:c.641-20041G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+6108G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7181C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.7181C>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
SCV000622719	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 23, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18573109, 19431188, 26677768, 28492532
SCV002080153	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Oct 30, 2020)	germline	clinical testing
SCV005039227	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 22, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18573109, 19431188, 26681312, 31843900, 34848827, 26677768, 33119476 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000622719

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 23, 2023)

germline

clinical testing

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

SCV002080153

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Oct 30, 2020)

germline

clinical testing

SCV005039227

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Mar 22, 2024)

germline

clinical testing

PubMed (7)
[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

Citations

PubMed

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

Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patients.

Austen B, Barone G, Reiman A, Byrd PJ, Baker C, Starczynski J, Nobbs MC, Murphy RP, Enright H, Chaila E, Quinn J, Stankovic T, Pratt G, Taylor AM.

Br J Haematol. 2008 Sep;142(6):925-33. doi: 10.1111/j.1365-2141.2008.07281.x. Epub 2008 Jun 28.

PubMed [citation]

PMID:: 18573109

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000622719.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2394 of the ATM protein (p.Ser2394Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 26677768). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127437). 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 disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 18573109, 19431188, 26677768). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 Natera, Inc., SCV002080153.1

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005039227.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: ATM c.7181C>T (p.Ser2394Leu) results in a non-conservative amino acid change located in the PIK-related kinase (IPR014009) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251332 control chromosomes. c.7181C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Ataxia-Telangiectasia (example, Lin_2015) and in settings of multigene panel testing for cancers (example, Susswein_2016). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete loss of ATM-kinase activity (Austen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18573109, 19431188, 31843900, 34848827, 26677768, 26681312, 33119476). ClinVar contains an entry for this variant (Variation ID: 127437). Based on the evidence outlined above, the variant was classified as likely 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

Last Updated: Nov 3, 2024

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