rs774925473

Positions:

• chr11-108309110-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3 PP1_Strong PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c.5763-1050A>G variant in ATM is an intronic variant which results in an intronic A>G substitution before coding exon 38 activating a cryptic splice site leading to alternative splicing. The variant has been observed to cause an insertion of 137 nucleotides of intronic sequence at position 5762 and a premature stop codon at position 1930. Some normal splicing has been reported in patients with ATM c.5763-1050A>G, thus, the splice effect is incomplete (PMIDs 8755918, 10330348, 11382771, 15174027, Ambry internal data). This variant has been detected in many individuals with Ataxia-Telangiectasia, some of whom were described as having a mild presentation and/or later age of onset (PMIDs 8755918, 26896183). The variant has also been reported to segregate with Ataxia-Telangiectasia in 6 affected family members from 3 families (PMIDs 8755918, 15174027). The variant has a minor allele frequency in gnomAD v2.1.1 of 0.00003 (PM2_Supporting, BS1, and BA1 are not met). ATM c.5763-1050A>G has been reported as a founder variant in the British Isles (PMID 9463314). 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 VCEP. (PVS1_Strong (RNA), PM3_Very Strong, PP1_Strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA115927/MONDO:0700270/020

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 0.274

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]

ATM (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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.
• PP1: 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.5763-1050A>G		intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5763-1050A>G		intron_variant			NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000236 AC: 3 AN: 127224 Hom.: 0 AF XY: 0.0000287 AC XY: 2 AN XY: 69670

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: 0.0000637

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000880 AC: 89 AN: 1010854 Hom.: 0 Cov.: 13 AF XY: 0.0000797 AC XY: 41 AN XY: 514350

Gnomad4 AFR exome AF: 0.0000410

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.0000879

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

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: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change falls in intron 38 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs774925473, gnomAD 0.01%). This variant has been observed in individual(s) with atypical ataxia-telangiectasia (characterized by later disease onset and/or slower disease progression and attenuated disease features than classical ataxia-telangiectasia) (PMID: 8755918, 8808599, 10330348, 21792198). 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 5762ins137, the 4-1-8 variant, IVS40-1050A>G, IVS40+1126A>G, IVS40ins137, and 5763ins130. ClinVar contains an entry for this variant (Variation ID: 3021). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2023	Variant summary: ATM c.5763-1050A>G is located at a deep intronic position with several computational tools predict a significant impact on normal splicing: Two predict the variant strengthens a cryptic 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in the inclusion of 137 base pairs of intronic sequence that is predicted to introduce a premature stop codon leading to a truncated protein (McConville_1996). The variant allele was found at a frequency of 2.4e-05 in 127224 control chromosomes. c.5763-1050A>G has been widely reported in the literature as a biallelic genotype in multiple individuals affected with milder features of Ataxia-Telangiectasia (example, Sutton_2004, McConville_1996). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATM: PM3:Very Strong, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2022	Non-canonical splice site variant demonstrated to result in two transcripts, one with a 137 nucleotide insertion which results in a frameshift, as well as some normal transcript (McConville et al., 1996; Teraoka et al., 1999); Published functional studies demonstrate a damaging effect: cells from individuals carrying this variant have been shown to have reduced ATM protein levels and ATM kinase activity compared to wildtype (Izatt et al., 1999; Stewart et al., 2001; Sutton et al., 2004; Reiman et al., 2011; Taylor et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 9463314, 23143971, 19823873, 17586848, 25040471, 21459046, 32623769, 19535770, 11382771, 15174027, 20301790, 8755918, 10234507, 10330348, 28008555, 15928302, 12082606, 30549301, 26896183, 32255556, 21792198) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 06, 2022	The c.5763-1050A>G intronic pathogenic mutation results from an A to G substitution 1050 nucleotides before coding exon 38 in the ATM gene. This mutation is known to activate a cryptic splice donor site that results in the insertion of 137 nucleotides between coding exon 37 and coding exon 38, leading to a premature stop codon that is expected to trigger nonsense-mediated mRNA decay (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stewart GS et al. J. Biol. Chem. 2001 Aug 10;276:30133-41). RNA studies have demonstrated that this alteration results in the same splicing event reported in the literature (Ambry internal data). Published studies have also shown that a normal mRNA transcript is produced from the affected allele, albeit at significantly reduced levels (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5). This mutation has been observed in multiple ataxia telangiectasia (AT) cohorts in both the homozygous and compound heterozygous state, and due to the preservation of some normal ATM protein expression, AT individuals with at least one copy of this mutation show a relatively less severe phenotype than individuals with classic AT (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586). One study showed that two siblings who were homozygous for this mutation and had exceptionally mild AT phenotypes still had approximately 11% of the level of ATM protein expected in normal cells (Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5). This mutation is considered a founder mutation originating in the British Isles, and is seen in the heterozygous state in approximately 15% of AT patients from the UK (Stewart GS et al. J. Biol. Chem. 2001 Aug 10;276:30133-41). Of note, this alteration is also designated as 5762ins137, IVS40-1050A>G, and IVS40+1126A>G in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 07, 2022	This variant causes an A to G nucleotide substitution at the -1050 position of intron 38 of the ATM gene. This variant is also known as IVS40-1050A>G, IVS40+1126A>G, IVS40ins137 and 5762ins137 in the literature. RNA studies have shown that this variant activates a cryptic splice donor site that results in the insertion of 137 nucleotides from the intronic sequence into the transcript (= 5762ins137), leading to a frameshift and premature protein truncation (PMID: 8755819; ClinVar SCV000581456.4). This variant is known to be a leaky splice mutation, allowing for the low-level expression of the full-length transcript and normal ATM protein (PMID: 8755819, 10234507, 15174027, 25040471). This variant has been reported in over forty homozygous and compound heterozygous individuals affected with mild, variant form of ataxia-telangiectasia (PMID: 8755918, 10234507, 10330348, 15174027, 21792198, 28008555, 30549301), consistent with the low-level expression of normal ATM protein from the mutant allele that carries this variant. This variant has been observed in multiple individuals affected with breast cancer, pancreatic cancer and melanoma (PMID: 19781682, 28008555, 32255556; Color internal data). This variant has been identified in 5/158620 chromosomes 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. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 25, 2024	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8755918, 11382771]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21792198, 8755918, 11382771, 26896183, 30549301]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 27, 2023

- -

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.5763-1050A>G variant in ATM is an intronic variant which results in an intronic A>G substitution before coding exon 38 activating a cryptic splice site leading to alternative splicing. The variant has been observed to cause an insertion of 137 nucleotides of intronic sequence at position 5762 and a premature stop codon at position 1930. Some normal splicing has been reported in patients with ATM c.5763-1050A>G, thus, the splice effect is incomplete (PMIDs 8755918, 10330348, 11382771, 15174027, Ambry internal data). This variant has been detected in many individuals with Ataxia-Telangiectasia, some of whom were described as having a mild presentation and/or later age of onset (PMIDs 8755918, 26896183). The variant has also been reported to segregate with Ataxia-Telangiectasia in 6 affected family members from 3 families (PMIDs 8755918, 15174027). The variant has a minor allele frequency in gnomAD v2.1.1 of 0.00003 (PM2_Supporting, BS1, and BA1 are not met). ATM c.5763-1050A>G has been reported as a founder variant in the British Isles (PMID 9463314). 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 VCEP. (PVS1_Strong (RNA), PM3_Very Strong, PP1_Strong) -

Ataxia - telangiectasia variant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2004

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 19, 2024

- -

ATM-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2024

The ATM c.5763-1050A>G variant is predicted to interfere with splicing. This variant, also known as 5762ins137, has been reported in the homozygous and compound heterozygous states in multiple unrelated individuals with ataxia telangiectasia (Table 3, McConville et al. 1996. PubMed ID: 8755918; Table SI, Jackson et al 2016. PubMed ID: 26896183; Supplementary Table 1, Schon et al 2019. PubMed ID: 30549301). In vitro studies show this variant activates a leaky cryptic splice site that introduces a 137 bp insertion of intronic sequence into affected ATM transcripts, although a small amount of normal ATM transcript and protein is still produced likely resulting in the milder phenotypic presentation seen in patients with ataxia telangiectasia (McConville et al 1996. PubMed ID: 8755918; Stewart GS et al 2001. PubMed ID: 11382771). This variant has also been reported in individuals with breast cancer and pancreatic cancer (Table S2, Tavtigian et al. 2009 PubMed ID: 19781682; Table 2, Pritzlaff et al 2016. PubMed ID: 28008555, Supplementary Table 2, Cremin C et al 2020. PubMed ID: 32255556). This variant is reported in 0.0080% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3021/). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	18
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs774925473; hg19: chr11-108179837;