NM_000051.4(ATM):c.7181C>T (p.Ser2394Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Aug 2, 2023
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:: RCV000494662.16

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:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000581469	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Aug 2, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18573109, 19431188, 26677768, 26681312, 37438524 Citation Link,
SCV002053077	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002537008	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Dec 18, 2020)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 26677768, 19431188, 18573109, 31843900 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000581469

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Aug 2, 2023)

germline

clinical testing

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

Citation Link,

SCV002053077

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 7, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002537008

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Dec 18, 2020)

germline

curation

PubMed (4)
[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, curation

Citations

PubMed

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK.

Genet Med. 2016 Aug;18(8):823-32. doi: 10.1038/gim.2015.166. Epub 2015 Dec 17. Erratum in: Genet Med. 2016 May;18(5):531-2. doi: 10.1038/gim.2016.21.

PubMed [citation]

PMID:: 26681312
PMCID:: PMC4985612

A framework for individualized splice-switching oligonucleotide therapy.

Kim J, Woo S, de Gusmao CM, Zhao B, Chin DH, DiDonato RL, Nguyen MA, Nakayama T, Hu CA, Soucy A, Kuniholm A, Thornton JK, Riccardi O, Friedman DA, El Achkar CM, Dash Z, Cornelissen L, Donado C, Faour KNW, Bush LW, Suslovitch V, Lentucci C, et al.

Nature. 2023 Jul;619(7971):828-836. doi: 10.1038/s41586-023-06277-0. Epub 2023 Jul 12.

PubMed [citation]

PMID:: 37438524
PMCID:: PMC10371869

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000581469.7

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

Description

The p.S2394L variant (also known as c.7181C>T), located in coding exon 48 of the ATM gene, results from a C to T substitution at nucleotide position 7181. The serine at codon 2394 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in trans with a truncating mutation in a patient with ataxia telangiectasia (Lin L et al. Stem Cell Reports. 2015 Dec; 5(6):1097-108). This alteration was identified with a truncating mutation in another individual with ataxia telangiectasia, however phase was not documented (Kim J et al. Nature, 2023 Jul;619:828-836). In vitro analysis indicate this variant has absent ATM kinase activity (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30; Austen B et al. Br. J. Haematol. 2008 Sep; 142(6):925-33). This alteration has also been detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med 2018 04;7(4):1349-1358). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be 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 Color Diagnostics, LLC DBA Color Health, SCV002053077.1

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

Description

This missense variant replaces serine with leucine at codon 2394 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant protein displays no detectable kinase activity in response to ionizing radiation (PMID: 18573109, 19431188). This variant has been reported in trans with a pathogenic ATM truncating variant in an individual affected with ataxia telangiectasia (PMID: 26677768). Cells derived from this individual expressed full-length ATM protein, but showed reduced X-irradiation (XR)-induced phosphorylation of CHEK2 and XR-induced gamma H2A.X nuclear puncta, suggesting little or no ATM kinase activity (PMID: 26677768). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is 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 Sema4, Sema4, SCV002537008.1

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

#	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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