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NM_000051.4(ATM):c.6807G>A (p.Gln2269=) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Jan 17, 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:
RCV000213885.18

Allele description [Variation Report for NM_000051.4(ATM):c.6807G>A (p.Gln2269=)]

NM_000051.4(ATM):c.6807G>A (p.Gln2269=)

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.6807G>A (p.Gln2269=)
Other names:
NM_000051.4(ATM):c.6807G>A; p.Gln2269=
HGVS:
  • NC_000011.10:g.108325544G>A
  • NG_009830.1:g.107713G>A
  • NG_054724.1:g.149289C>T
  • NM_000051.4:c.6807G>AMANE SELECT
  • NM_001330368.2:c.641-16473C>T
  • NM_001351110.2:c.*38+9676C>T
  • NM_001351834.2:c.6807G>A
  • NP_000042.3:p.Gln2269=
  • NP_000042.3:p.Gln2269=
  • NP_001338763.1:p.Gln2269=
  • LRG_135t1:c.6807G>A
  • LRG_135:g.107713G>A
  • LRG_135p1:p.Gln2269=
  • NC_000011.9:g.108196271G>A
  • NM_000051.3:c.6807G>A
Links:
dbSNP: rs587780638
NCBI 1000 Genomes Browser:
rs587780638
Molecular consequence:
  • NM_001330368.2:c.641-16473C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001351110.2:c.*38+9676C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000051.4:c.6807G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001351834.2:c.6807G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000278570Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely pathogenic
(Jan 17, 2024)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001358591Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jan 9, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

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

Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia.

Schon K, van Os NJH, Oscroft N, Baxendale H, Scoffings D, Ray J, Suri M, Whitehouse WP, Mehta PR, Everett N, Bottolo L, van de Warrenburg BP, Byrd PJ, Weemaes C, Willemsen MA, Tischkowitz M, Taylor AM, Hensiek AE.

Ann Neurol. 2019 Feb;85(2):170-180. doi: 10.1002/ana.25394.

PubMed [citation]
PMID:
30549301
PMCID:
PMC6590299
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000278570.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The c.6807G>A variant (also known as p.Q2269Q), located in coding exon 45 of the ATM gene, results from a G to A substitution at nucleotide position 6807. This nucleotide substitution does not change the glutamine at codon 2269. However, this change occurs in the last base pair of coding exon 45, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in the literature an individual diagnosed with variant ataxia-telangiectasia (A-T) (Schon K et al. Ann. Neurol., 2019 02;85:170-180). In addition, this alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

From Color Diagnostics, LLC DBA Color Health, SCV001358591.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This synonymous variant substitutes the conserved G with A at the last nucleotide of exon 46 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies demonstrating abnormal splicing have been reported in ClinVar (ClinVar variation ID: 135775). This variant has been reported in trans with a pathogenic ATM truncation mutation in an individual affected with an attenuated form of ataxia telangiectasia (PMID: 30549301). The lymphoblastoid cell line derived from this individual has shown some normal ATM protein with residual kinase activity, which may be attributed to a leaky splice site mutation. This variant has also been reported in individuals affected with breast cancer (PMID: 28779002; Color internal data). 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.

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

Last Updated: Feb 8, 2025