rs1060501610

Variant names:

• chr11-108253830-G-GT
• rs1060501610
• NM_000051.4:c.1915_1916insT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.1915_1916insT​(p.Asp639ValfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.187

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 11-108253830-G-GT is Pathogenic according to our data. Variant chr11-108253830-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407572.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.1915_1916insT	p.Asp639ValfsTer2	frameshift_variant	Exon 13 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1915_1916insT	p.Asp639ValfsTer2	frameshift_variant	Exon 13 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 11, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ATM gene demonstrated a single base pair insertion in exon 13, c.1915_1916insT. This sequence change creates a frameshift resulting in a premature stop codon 1 amino acid residue downstream of the variant, p.Asp639Valfs*2. The p.Asp639Valfs*2 change is predicted to result in an absent or disrupted protein product. This sequence change has not previously been described in patients with ATM-related disorders and has been described in the gnomAD database in one individual with an overall frequency of 0.003% (dbSNP rs1060501610). While the p.Asp639Valfs*2 change has not previously been described in the literature, loss-of-function variants in the ATM gene are known to be pathogenic (PMIDs: 23807571, 25614872). These collective evidences suggest that this sequence change is a likely pathogenic sequence change, however functional studies have not been performed to prove this conclusively. -

Feb 01, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This insertion of one nucleotide in ATM is denoted c.1915_1916insT at the cDNA level and p.Asp639ValfsX2 (D639VfsX2) at the protein level. The normal sequence, with the base that is inserted in brackets, is AAAG[insT]ATAA. The insertion causes a frameshift which changes an Aspartic Acid to a Valine at codon 639, and creates a premature stop codon at position 2 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this insertion to be a likely pathogenic variant. -

Familial cancer of breast Pathogenic:2

Jan 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 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. -

Ataxia-telangiectasia syndrome Pathogenic:1

Jul 17, 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.Asp639Valfs*2) 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 present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 407572). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 23, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1915_1916insT pathogenic mutation, located in coding exon 12 of the ATM gene, results from an insertion of one nucleotide at position 1915, causing a translational frameshift with a predicted alternate stop codon (p.D639Vfs*2). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501610; hg19: chr11-108124557;