NM_000051.4(ATM):c.7788+3A>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 6, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001692142.13

Allele description [Variation Report for NM_000051.4(ATM):c.7788+3A>G]

NM_000051.4(ATM):c.7788+3A>G

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.7788+3A>G

HGVS:

NC_000011.10:g.108332040A>G
NG_009830.1:g.114209A>G
NG_054724.1:g.142793T>C
NM_000051.4:c.7788+3A>GMANE SELECT
NM_001330368.2:c.641-22969T>C
NM_001351110.2:c.*38+3180T>C
NM_001351834.2:c.7788+3A>G
LRG_135t1:c.7788+3A>G
LRG_135:g.114209A>G
NC_000011.9:g.108202767A>G
NM_000051.3:c.7788+3A>G

Links:

dbSNP: rs869312788

NCBI 1000 Genomes Browser:

rs869312788

Molecular consequence:

NM_000051.4:c.7788+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001330368.2:c.641-22969T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+3180T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351834.2:c.7788+3A>G - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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
SCV001911486	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	criteria provided, single submitter (Feliubadaló L et al. (Clin Chem 2021))	Likely pathogenic (Jun 17, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33011440, 33280026
SCV002674706	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 6, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001911486

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

criteria provided, single submitter

(Feliubadaló L et al. (Clin Chem 2021))

Likely pathogenic
(Jun 17, 2020)

germline

clinical testing

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

SCV002674706

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 6, 2022)

germline

clinical testing

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

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
European caucasoid	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients.

Feliubadaló L, Moles-Fernández A, Santamariña-Pena M, Sánchez AT, López-Novo A, Porras LM, Blanco A, Capellá G, de la Hoya M, Molina IJ, Osorio A, Pineda M, Rueda D, de la Cruz X, Diez O, Ruiz-Ponte C, Gutiérrez-Enríquez S, Vega A, Lázaro C.

Clin Chem. 2021 Mar 1;67(3):518-533. doi: 10.1093/clinchem/hvaa250.

PubMed [citation]

PMID:: 33280026

Improving Genetic Testing in Hereditary Cancer by RNA Analysis: Tools to Prioritize Splicing Studies and Challenges in Applying American College of Medical Genetics and Genomics Guidelines.

Rofes P, Menéndez M, González S, Tornero E, Gómez C, Vargas-Parra G, Montes E, Salinas M, Solanes A, Brunet J, Teulé A, Capellá G, Feliubadaló L, Del Valle J, Pineda M, Lázaro C.

J Mol Diagn. 2020 Dec;22(12):1453-1468. doi: 10.1016/j.jmoldx.2020.09.007. Epub 2020 Oct 1.

PubMed [citation]

PMID:: 33011440

Details of each submission

From Spanish ATM Cancer Susceptibility Variant Interpretation Working Group, SCV001911486.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European caucasoid	1	not provided	not provided	clinical testing	PubMed (2)

Description

The c.7788+3A>G variant it is predicted to disrupt the donor splice site for intron 52. The skipping of exon 52 predicted by default would result in an in-frame deletion of 53 codons (r. .7630_7788del, p.Leu2544_Glu2596del, PP3). Splicing studies performed by two independent laboratories with heterozygous carrier RNA from breast cancer patients confirmed the presence of the predicted transcript with a band intensity comparable to that of the wild-type band (r.7630_7927del p.Leu2544Lysfs*3, O. Díez, unpublished and PMID: 33011440). Sanger sequencing also revealed a very minor transcript corresponding to the out-of-frame skipping of exons 52 and 53 (PMID: 33011440). Although the major transcript is in frame, the skipped exon 52 is located in the FAT domain and contains the nucleotides deleted in the pathogenic in-frame deletion pathogenic variant c.7638_7646del. These RNA results and their expected consequence allow for a funtional supporting code (PS3_Supporting). The c.7788+3A>G variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It has been reported in one ataxia-telangiectasia proband in trans with c.5932G > T (p.Glu1978*), which awards it with 1 point as per ClinGen SVI Recommendation for in trans Criterion (PM3, De Stefano, 2016 https://doi.org/10.1515/labmed-2016-0018). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PM3 + PP3 + PS3_Supporting (PMID: 33280026).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Ambry Genetics, SCV002674706.2

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

Description

The c.7788+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 51 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In a study involving RNA extraction for RT-PCR and Sanger sequencing of 10 hereditary cancer genes, incomplete disruption of the natural splice site was observed for this alteration (Rofes P et al. J Mol Diagn, 2020 12;22:1453-1468). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: Sep 16, 2024

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