rs267606668

chr11-108332848-TG-GC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):c.7875_7876delinsGC(p.Asp2625_Ala2626delinsGluPro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 6.92

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_000051.4 (ATM) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108332848-TG-GC is Pathogenic according to our data. Variant chr11-108332848-TG-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7875_7876delinsGC	p.Asp2625_Ala2626delinsGluPro	missense_variant	53/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7875_7876delinsGC	p.Asp2625_Ala2626delinsGluPro	missense_variant	53/63		NM_000051.4	P1

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/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:5 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	Variant summary: ATM c.7875_7876delinsGC (p.Asp2625_Ala2626delinsGluPro) results in an in-frame deletion-insertion that is predicted to delete two amino acids and insert to amino acids from the encoded protein. The variant was absent in 250852 control chromosomes (gnomAD). c.7875_7876delinsGC has been reported in the literature in multiple bi-allelic individuals affected with Ataxia-Telangiectasia (example: Verhagen_2012). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 30, 2004	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This variant, c.7875_7876delinsGC, is a complex sequence change that results in the substitution of 2 amino acid(s) in the ATM protein (p.Asp2625_Ala2626delinsGluPro). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with ataxia telangiectasia (PMID: 9521587, 10980530, 19535770, 22213089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as a double missense variant, D2625E and A2626P on the same chromosome. ClinVar contains an entry for this variant (Variation ID: 3030). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATM function (PMID: 22213089). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Dec 05, 2022	ACMG criteria used to clasify this variant: PS4, PS3_MOD, PM3, PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 02, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9521587, 10980530, 19535770]. -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 03, 2021	The c.7875_7876delTGinsGC variant (also known as p.D2625_A2626delinsEP), located in coding exon 52 of the ATM gene, results from the deletion of TG and the insertion of GC at nucleotide positions 7875 and 7876. This causes amino acid substitutions at two highly-conserved codons: the aspartic acid at codon 2625 is replaced by glutamic acid and the alanine at codon 2626 is replaced by proline. This alteration has been reported in multiple ataxia-telangiectasia (AT) families, both homozygous and in trans with known pathogenic mutations (van Belzen MJ et al. Hum. Genet. 1998 Feb;102(2):187-91; Li A and Swift M. Am. J. Med. Genet. 2000 May;92(3):170-7; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun; 70(2):122-33; Laake K et al. Hum. Mutat. 2000 Sep;16(3):232-46; Dörk T et al. Am. J. Med. Genet. A 2004 Apr;126A(3):272-7; Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71; Driessen GJ et al. J. Allergy Clin. Immunol. 2013 May;131(5):1367-75.e9). In one study, this variant was associated with complete absence of ATM protein in one homozygous AT patient (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70(2):122-33), while a second study detected ATM protein, but no ATM kinase activity in four homozygous AT patients (Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 01, 2022	This missense variant replaces aspartic acid and alanine at codons 2625 and 2626 of the ATM protein with glutamic acid and proline. This variant has been reported in the homozygous state or compound heterozygous state with another pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 9521587, 10873394, 11104561, 15054841, 17985259, 19535770, 21778326, 22213089, 25037873, 25122203, 30549301, 31050087). Cells derived from some of these individuals have shown reduced ATM kinase activity (PMID: 22213089, 30549301, 31050087). In a large international case-control study, this variant was reported in 8/60466 breast cancer cases and 7/53461 controls (PMID: 33471991). This variant has also been reported in an individual affected with pancreatic cancer (PMID: 29922827). 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606668; hg19: chr11-108203575;