rs752135143

chr11-108229328-G-Achr11-108229328-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000051.4(ATM):c.331+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.24

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108229328-G-A is Pathogenic according to our data. Variant chr11-108229328-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 230851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108229328-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.331+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.331+5G>A		splice_donor_5th_base_variant, intron_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249372 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134892

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: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456716 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724808

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000457 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2023	Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and published functional studies demonstrate this variant causes skipping of exon 4, with reduced or absent ATM protein and kinase activity (Verhagen et al., 2009; Verhagen et al., 2012; Nakamura et al., 2012; van Os et al., 2017); Observed in the homozygous or compound heterozygous state in several individuals with ataxia-telangiectasia (Verhagen et al., 2009; Verhagen et al., 2012; Nakamura et al., 2012; Chen et al., 2013; van Os et al., 2017); Observed in the heterozygous state in individuals with prostate or ovarian cancer (Lilyquist et al., 2017; Darst et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Also reported as IVS6+5G>A using alternate intron nomenclature; This variant is associated with the following publications: (PMID: 23726790, 22006793, 19535770, 23566627, 22213089, 28126470, 19705055, 30549301, 29288088, 32853339, 29922827, 30850667, 37649078, 28888541) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The c.331+5G>A variant in ATM has been reported in at least 2 homozygous and 2 compound heterozygous individuals with ataxia-telangiectasia and segregated with disease in at least 1 affected family member (Verhagen 2009 PMID: 19535770, Nakamura 2012 PMID: 22006793, Verhagen 2012 PMID: 22213089, Chen 2013 PMID: 23726790). It has also been reported in ClinVar (Variation ID 230851) but was absent from large population studies. This variant is located in the 5'/3' splice region. Computational tools do not provide strong support for a splicing impact, however, In vitro functional studies (including using patient tissue) support exon 6 (exon 5 on NM000051) skipping (introducing a frameshift) and an impact on ATM function (Verhagen 2009 PMID: 19535770, Nakamura 2012 PMID: 22006793). Loss of function of the ATM gene is an established disease mechanism in autosomal recessive ataxia telangiectasia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ataxia telangiectasia. ACMG/AMP Criteria applied: PM2_supporting, PVS1, PM3_Strong. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Splice variant predicted to produce a truncated protein by alternate splicing. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19535770). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.98). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 19535770, 22213089, 23726790). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 23726790). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000230851 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change falls in intron 4 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 (rs752135143, gnomAD 0.0009%). This variant has been observed in individuals with ataxia-telangiectasia (PMID: 19535770, 22006793, 22213089, 23726790). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 230851). 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: 19535770). 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 4 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. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 14, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 09, 2024	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data, PMID: 17726045]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19535770, 22213089, 23726790]. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 23, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2021

The c.331+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 3 in the ATM gene. In one study, this alteration was detected as homozygous in two related individuals diagnosed with ataxia-telangiectasia (A-T) and was correlated with decreased ATM protein levels and kinase activity (Verhagen MM et al, Neurology 2009 Aug; 73(6):430-7). This alteration has also been identified in several individuals with A-T as a compound heterozygous state (Morio T et al. Int. J. Hematol., 2009 Nov;90:455-462; Nakamura K et al. Hum. Mutat., 2012 Jan;33:198-208; Verhagen MM et al. Hum. Mutat., 2012 Mar;33:561-71; Chen Z et al. Neurobiol Aging, 2013 Oct;34:2442.e11-7). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		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: rs752135143; hg19: chr11-108100055;