NM_000051.4:c.3754_3756delTATinsCA

Variant names:

• chr11-108284234-TAT-CA
• rs786201886
• NM_000051.4:c.3754_3756delTATinsCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.3754_3756delTATinsCA​(p.Tyr1252GlnfsTer4) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1252H) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.65
• Publications: 2 publications found

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108284234-TAT-CA is Pathogenic according to our data. Variant chr11-108284234-TAT-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 185042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.3754_3756delTATinsCA	p.Tyr1252GlnfsTer4	frameshift_variant, missense_variant	Exon 26 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3754_3756delTATinsCA	p.Tyr1252GlnfsTer4	frameshift_variant, missense_variant	Exon 26 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Nov 16, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 19, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

​The c.3754_3756delTATinsCA pathogenic mutation, located in coding exon 25 of the ATM gene, results from the deletion of 3 nucleotides and the insertion of 2 nucleotides at positions 3754-3756, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Aug 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant replaces 3 nucleotides with 2 new nucleotides in exon 26 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals of a family affected with breast cancer or thyroid cancer (PMID: 27913932). This variant has not been identified 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. -

Ataxia-telangiectasia syndrome Pathogenic:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr1252Glnfs*4) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and/or thyroid cancer (PMID: 27913932). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1049082). For these reasons, this variant has been classified as Pathogenic. -

ATM-related disorder Pathogenic:1

Oct 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.3754_3756delinsCA variant is predicted to result in a frameshift and premature protein termination (p.Tyr1252Glnfs*4). This variant was reported in individuals with breast or thyroid cancer and has been seen to segregate with disease in families (Tavera-Tapia et al. 2017. PubMed ID: 27913932; Bonache et al. 2018. PubMed ID: 30306255; Renault et al. 2018. PubMed ID: 29665859). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/185042/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Oct 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27913932, 28152038, 29665859, 30306255) -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Tyr1252GlnfsX4 variant was not identified in the literature nor was it identified in the dbSNP, Cosmic, MutDB, LOVD 3.0, databases. The variant was identified in the ClinVar (reported 3x as pathogenic by Ambry Genetics, GeneDx, Invitae) database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3754_3756delinsCA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1252 and leads to a premature stop codon, 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM related cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786201886; hg19: chr11-108154961;