NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 18, 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:: RCV000159742.20

Allele description [Variation Report for NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys)]

NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys)

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.6095G>A (p.Arg2032Lys)

Other names:

p.R2032K:AGA>AAA

HGVS:

NC_000011.10:g.108315911G>A
NG_009830.1:g.98080G>A
NG_054724.1:g.158922C>T
NM_000051.4:c.6095G>AMANE SELECT
NM_001330368.2:c.641-6840C>T
NM_001351110.2:c.*39-6840C>T
NM_001351834.2:c.6095G>A
NP_000042.3:p.Arg2032Lys
NP_000042.3:p.Arg2032Lys
NP_001338763.1:p.Arg2032Lys
LRG_135t1:c.6095G>A
LRG_135:g.98080G>A
LRG_135p1:p.Arg2032Lys
NC_000011.9:g.108186638G>A
NM_000051.3:c.6095G>A
p.R2032K

Protein change:

R2032K

Links:

dbSNP: rs139770721

NCBI 1000 Genomes Browser:

rs139770721

Molecular consequence:

NM_001330368.2:c.641-6840C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-6840C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6095G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6095G>A - 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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Gene ID:851857

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214152	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 29, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10817650, 16266405, 25614872, 26506520, 27159176, 9887333 Citation Link,
SCV000682303	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 18, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 9443866, 9887333, 10330348, 10817650, 10980530, 16266405, 22585167, 25614872, 26506520, 27159176, 29678143, 31012270, 34377931, 36029002, 37445923, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214152

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 29, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000682303

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 18, 2023)

germline

clinical testing

PubMed (16)
[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

Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations.

Telatar M, Teraoka S, Wang Z, Chun HH, Liang T, Castellvi-Bel S, Udar N, Borresen-Dale AL, Chessa L, Bernatowska-Matuszkiewicz E, Porras O, Watanabe M, Junker A, Concannon P, Gatti RA.

Am J Hum Genet. 1998 Jan;62(1):86-97.

PubMed [citation]

PMID:: 9443866
PMCID:: PMC1376800

Characterization of ATM gene mutations in 66 ataxia telangiectasia families.

Sandoval N, Platzer M, Rosenthal A, Dörk T, Bendix R, Skawran B, Stuhrmann M, Wegner RD, Sperling K, Banin S, Shiloh Y, Baumer A, Bernthaler U, Sennefelder H, Brohm M, Weber BH, Schindler D.

Hum Mol Genet. 1999 Jan;8(1):69-79.

PubMed [citation]

PMID:: 9887333

See all PubMed Citations (16)

Details of each submission

From Ambry Genetics, SCV000214152.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The c.6095G>A pathogenic mutation (also known as p.R2032K), located in coding exon 40 of the ATM gene, results from a G to A substitution at nucleotide position 6095. The amino acid change results in arginine to lysine at codon 2032, an amino acid with highly similar properties. This alteration has been described as a founder mutation in the Polish population and has been detected in conjunction with a second mutation in numerous probands with ataxia-telangiectasia (A-T) (Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64. Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Beier R et al. Bone Marrow Transplant. 2016 09;51:1271-4). This mutation has also been reported in high-risk breast cancer cohorts (Schubert S et al. Int. J. Cancer 2018 Nov; Podralska M et al. Mol Genet Genomic Med 2014 Nov;2(6):504-11). This change occurs in the highly-conserved last base pair of coding exon 40, which makes it likely to have some effect on normal mRNA splicing. RT-PCR analysis performed on RNA isolated from an A-T individual with this alteration was reported to result in exon skipping (Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). RNA studies have shown the same abnormal splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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, SCV000682303.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This variant causes a G to A nucleotide substitution at the last nucleotide of exon 41 of the ATM gene and replaces arginine with lysine at codon 2032 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies using carrier-derived RNA have shown that this variant causes the skipping of exon 41 (also known as exon 43 in the literature), creating a premature translation stop signal (PMID: 9443866, 9887333, 10980530). The aberrant transcript is expected to result in an absent or non-functional protein product. Functional cytometric analysis of cells from individuals carrying this variant and affected with chronic lymphocytic leukemia showed decreased kinase activity (PMID: 36029002). This variant has been described as a recurrent mutation in the Polish population (PMID: 9443866, 16266405) and has been reported in many individuals affected with ataxia-telangiectasia (PMID: 9443866, 9887333, 10330348, 10817650, 10980530, 16266405, 25614872, 27159176) or adult-onset focal dystonia (PMID: 37445923). This variant has also been reported in individuals affected breast cancer, prostate cancer, pancreatic cancer or gastric cancer (PMID: 22585167, 26506520, 29678143, 31012270, 34377931). In a large international case-control study, this variant was reported in 9/60466 breast cancer cases and 4/53461 controls (OR=1.989, 95%CI 0.613 to 6.461, p-value=0.279; PMID: 33471991). This variant has been identified in 7/251394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as 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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