NM_000051.4(ATM):c.6056A>G (p.Tyr2019Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 21, 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:: RCV000216689.20

Allele description [Variation Report for NM_000051.4(ATM):c.6056A>G (p.Tyr2019Cys)]

NM_000051.4(ATM):c.6056A>G (p.Tyr2019Cys)

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.6056A>G (p.Tyr2019Cys)

HGVS:

NC_000011.10:g.108315872A>G
NG_009830.1:g.98041A>G
NG_054724.1:g.158961T>C
NM_000051.4:c.6056A>GMANE SELECT
NM_001330368.2:c.641-6801T>C
NM_001351110.2:c.*39-6801T>C
NM_001351834.2:c.6056A>G
NP_000042.3:p.Tyr2019Cys
NP_000042.3:p.Tyr2019Cys
NP_001338763.1:p.Tyr2019Cys
LRG_135t1:c.6056A>G
LRG_135:g.98041A>G
LRG_135p1:p.Tyr2019Cys
NC_000011.9:g.108186599A>G
NM_000051.3:c.6056A>G

Protein change:

Y2019C

Links:

dbSNP: rs876658415

NCBI 1000 Genomes Browser:

rs876658415

Molecular consequence:

NM_001330368.2:c.641-6801T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-6801T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6056A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6056A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; 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
SCV000273593	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jul 1, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19431188, 22649200, 26896183, 28779002 Citation Link,
SCV000911956	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 21, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19431188, 22649200, 30549301, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000273593

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jul 1, 2024)

germline

clinical testing

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

Citation Link,

SCV000911956

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 21, 2024)

germline

clinical testing

PubMed (4)
[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

Longitudinal analysis of the neurological features of ataxia-telangiectasia.

Jackson TJ, Chow G, Suri M, Byrd P, Taylor MR, Whitehouse WP.

Dev Med Child Neurol. 2016 Jul;58(7):690-7. doi: 10.1111/dmcn.13052. Epub 2016 Feb 19.

PubMed [citation]

PMID:: 26896183

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

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000273593.9

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

Description

The p.Y2019C variant (also known as c.6056A>G), located in coding exon 40 of the ATM gene, results from an A to G substitution at nucleotide position 6056. The tyrosine at codon 2019 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in a compound heterozygous state along with the p.L2338P (c.7013T>C) alteration in a seven-year old female with ataxia-telangiectasia. Functional impact of these alterations was assessed via western blot and indicated 0% ATM protein expression (Carney EF et al, J. Immunol. 2012 Jul; 189(1):261-8). Another study assessed the stability and kinase activity of multiple ATM variants and found that this variant resulted in ATM expression but with no detectable downstream kinase activity (Barone G et al, Hum. Mutat. 2009 Aug; 30(8):1222-30). This variant was also identified in 1 of 13087 breast cancer cases and 0 of 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 Nov;54:732-741). 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, SCV000911956.3

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

Description

This missense variant replaces tyrosine with cysteine at codon 2019 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant disrupts kinase activity (PMID: 19431188, 22649200). This variant has been observed in the compound heterozygous state in individuals affected with autosomal recessive ataxia-telangiectasia (PMID: 22649200, 30549301; DOI: 10.17863/CAM.112012), indicating that this variant contributes to disease. 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

Last Updated: Jul 5, 2025

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