rs587776551

Positions:

• chr11-108281168-G-A
• chr11-108281168-G-C
• chr11-108281168-G-T

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3 PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c. 3576G>A (p.Lys1192=) variant is a synonymous (silent) variant in ATM. It is predicted to cause skipping of a biologically-relevant-exon, resulting in an in-frame deletion that is predicted to escape nonsense mediated decay. This prediction is confirmed by RNA analysis (PMID:9887333, 21965147; Ambry internal data). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID:21965147, 26896183, 30819809). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000035 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1_Strong (RNA), PM3_Very Strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA193897/MONDO:0700270/020

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:26
• Conservation: PhyloP100: 8.97

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 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.3576G>A	p.Lys1192Lys	splice_region_variant, synonymous_variant	24/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3576G>A	p.Lys1192Lys	splice_region_variant, synonymous_variant	24/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251126 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135794

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461228 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726966

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151980 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74238

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change affects codon 1192 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587776551, gnomAD 0.004%). This variant has been observed in individuals with ataxia-telangiectasia and early-onset breast and thyroid cancer (PMID: 8845835, 9887333, 17124347, 19691550, 22071889, 27599564). This variant is also known as 3403del174. ClinVar contains an entry for this variant (Variation ID: 3035). 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: 22071889). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 24, but is expected to preserve the integrity of the reading-frame (PMID: 9887333; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 24, 2018	Variant summary: ATM c.3576G>A (p.Lys1192Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. An experimental study, Demuth_2011, supports these predictions by finding that this variant is associated with an in-frame exclusion of exon 26 from the mRNA. The variant allele was found at a frequency of 1.6e-05 in 246056 control chromosomes (gnomAD). The variant, c.3576G>A, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Chessa_2009, Demuth_2011). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -
Likely pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 08, 2016	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2022	Located at the last nucleotide of exon 24 (also known as exon 26 in the literature) and demonstrated to result in abnormal splicing leading to skipping of exon 24 and/or exon 24-25 (Sandoval et al., 1999; Teraoka et a., 1999; Demuth et al., 2011; Jacquemin et al., 2012); Published functional studies demonstrate a damaging effect: reduced or absent protein expression and kinase activity (Sandoval et al., 1999; Teraoka et al., 1999; Demuth et al., 2011; Jacquemin et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer and other cancers (Prodosmo et al., 2016; Huang et al., 2018; Akcay et al., 2020; Asadollahi et al., 2020; Pastorino et al., 2020); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21965147, 10873394, 16941484, 17124347, 9463314, 21665257, 16189143, 11382771, 22927201, 27664052, 17910737, 22071889, 12552559, 10330348, 9450906, 9792409, 9443866, 22213089, 11606401, 15503472, 19691550, 8845835, 30819809, 30620386, 9887333, 29625052, 31741144, 32658311, 32325837, 32748564, 26896183, 33624863, 27599564) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ATM: PM3:Very Strong, PM2, PP3, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2024	The ATM c.3576G>A (p.Lys1192=) synonymous variant has been reported in the published literature in compound heterozygotes and homozygotes individuals with ataxia-telangiectasia (PMIDs: 35257272 (2022), 30819809 (2019), 27599564 (2016), 22213089 (2011)). Functional evidence indicates that this variant results in aberrant mRNA splicing and impacts protein function (PMIDs: 21965147 (2011), 22071889 (2011), 9887333 (1999), 9497252 (1998)). The frequency of this variant in the general population, 0.000016 (4/251126 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper ATM mRNA splicing. Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PS3_MOD, PM3_VSTR -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 22, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9887333]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8698354]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Jun 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 01, 2022	The c.3576G>A pathogenic mutation (also known as p.K1192K) is located in coding exon 23 of the ATM gene. This pathogenic mutation results from a G to A substitution at nucleotide position 3576. This nucleotide substitution does not change the lysine at codon 1192. However, this change occurs in the last base pair of coding exon 23 which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported frequently in individuals with a clinical diagnosis of ataxia telangiectasia, and has been observed in the homozygous state in individuals with severe disease (Chessa L et al. Ann. Hum. Genet. 2009 Sep;73(Pt 5):532-9; Cavalieri S et al. Ann. Hum. Genet. 2008 Jan;72(Pt 1):10-8; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). This alteration has been demonstrated to cause abnormal splicing, resulting in skipping of exon 23 (referred to as exon 26 in the literature) (Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Furthermore, several studies have shown that this alteration results in decreased/absent ATM protein expression and very low ATM kinase activity (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62:551-61; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, c.3576G>A is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2022	This variant alters the conserved c.G at the last nucleotide position of exon 24 of the ATM gene. Splice site prediction tools suggest that this variant may impact RNA splicing. Functional RNA studies have shown that this variant causes an in-frame skipping of exon 24 (hence, known as 3403del174 and p.Ser1135_Lys1192del58 in the literature) or out-of-frame skipping of exons 24 and 25 (PMID: 9887333, 21965147). This variant has been shown to significantly affect protein stability and/or kinase activity (PMID: 9887333, 21965147, 22071889). This variant has been reported in multiple individuals and families affected with ataxia-telangiectasia and is recurrent in Turkish and Italian populations (PMID: 9792409, 9887333, 16941484, 17124347, 19691550, 22071889, 30819809, 31741144, 34107524, 35257272). This variant has also been reported in two individuals affected with breast cancer (PMID: 27599564, 29665859). This variant has been identified in 4/251126 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 15, 2020

- -

ATM-related cancer predisposition Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Nov 26, 2024

The c. 3576G>A (p.Lys1192=) variant is a synonymous (silent) variant in ATM. It is predicted to cause skipping of a biologically-relevant-exon, resulting in an in-frame deletion that is predicted to escape nonsense mediated decay. This prediction is confirmed by RNA analysis (PMID: 9887333, 21965147; Ambry internal data). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 21965147, 26896183, 30819809). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000035 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1_Strong (RNA), PM3_Very Strong) -

Malignant tumor of pancreas Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Karaiskakio Foundation

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776551; hg19: chr11-108151895; COSMIC: COSV105124830;