rs786202935

chr11-108257477-A-Gchr11-108257477-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000051.4(ATM):c.2251-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,402 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:3
• Conservation: PhyloP100: 2.87

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 Uncertain_significance. Variant got 4 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 11-108257477-A-G is Pathogenic according to our data. Variant chr11-108257477-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186418.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=3, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2251-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2251-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460402 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726554

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 12, 2024	The c.2251-4A>G intronic variant results from an A to G substitution 4 nucleotides upstream from coding exon 14 in the ATM gene. This variant has been reported in conjunction with a pathogenic finding in this same gene (confirmed in trans) in three siblings with features of variant ataxia-telangiectasia (AT) including head dystonia, mild dysarthria, late onset ataxia, and breast cancer before age 40 (Asadollahi R et al. Mol Genet Genomic Med, 2020 10;8:e1409). This alteration, designated as IVS14-4A>G, has also been reported in conjunction with a second ATM alteration in a patient with classical AT phenotype (Mutlu-Albayrak H et al. Neurogenetics, 2020 Jan;21:59-66). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data, Asadollahi R et al. Mol Genet Genomic Med, 2020 10;8:e1409). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 02, 2023	This variant causes an A to G nucleotide substitution at the -4 position of intron 14 of the ATM gene. Splice site prediction tools suggest that this variant may create a new splice acceptor site and have a significant impact on RNA splicing. The use of the new splice acceptor site has been observed in a study using carrier-derived RNA, although the wild-type transcript was also observed, suggesting the impact may be incomplete (PMID: 32748564). The aberrant RNA transcript is expected to create a premature translation stop signal and result in an absent or non-functional protein product. Abnormal RNA splicing has also been reported in ClinVar (SCV000216769.6). This variant has been reported in trans with another pathogenic splice ATM variant (c.3576G>A) in three siblings of a family (PMID: 32748564). One male sibling is affected with late-onset progressive ataxia in his 30s. Two female siblings are affected with breast cancer at the age of 39 and 40 years and one of them has shown severe reaction post-radiotherapy. Another female sibling of the family who is heterozygous for this variant is unaffected at the age of 45. This variant has been reported in other individuals with classic ataxia telangiectasia (PMID: 31741144), or with personal and/or family history of breast cancer (PMID: 31159747; DOI: 10.7197/cmj.vi.623656). 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. The incomplete impact on RNA splicing and lack of classic ataxia telangiectasia phenotype in carriers suggest that this variant may be hypomorphic. -

Ataxia-telangiectasia syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 06, 2023	Variant summary: ATM c.2251-4A>G 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: one predicts the variant abolishes a 3' acceptor site, and one predicts the variant weakens the same 3' acceptor site. Additionally, four predict the variant creates a 3' acceptor site three nucleotides upstream. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to the introduction of three nucleotides (TAG) which results in a premature stop codon (e.g., Asadollahi_2020). The variant was absent in 250502 control chromosomes (gnomAD). c.2251-4A>G has been reported in the literature in compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g., Mutlu-Albayrak_2020, Asadollahi_2020, Karaasian_2023 (no PMID, Research Square preprint)) as well as individuals with a personal or family history of ATM-related cancers (e.g., Tsaousis_2019, Asadollahi_2020, Akcay_2021, Ozdemir_2023). The variant was reported to segregate with disease in at least one family (e.g., Asadollahi_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect as the studies were only conducted in compound heterozygous patient cells (e.g., Asadollahi_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 32748564, 31741144, 37453313, 31159747). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely pathogenic, n = 3; VUS, n = 3), although all VUS classifications were reported in ClinVar to have been evaluated prior to the publication of all evidence ascertained in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change falls in intron 14 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 not present in population databases (gnomAD no frequency). This variant has been observed in individuals with ataxia-telangiectasia, breast cancer, and in individual(s) undergoing genetic testing for hereditary cancer (PMID: 31159747, 31741144, 32748564). This variant is also known as IVS14-4A>G. ClinVar contains an entry for this variant (Variation ID: 186418). Studies have shown that this variant results in gain of a de novo splice site and introduces a premature termination codon (PMID: 32748564; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 25, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 17, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31741144, 32748564]. Functional studies indicate this variant impacts protein function [PMID: 32748564]. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 28, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	This variant is denoted ATM c.2251-4A>G or IVS14-4A>G and consists of an A>G nucleotide substitution at the -4 position of intron 14 of the ATM gene. In-silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether ATM c.2251-4A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs786202935; hg19: chr11-108128204; COSMIC: COSV53734600; COSMIC: COSV53734600;