NM_000051.4:c.1235+3A>G

Variant names:

• chr11-108249105-A-G
• rs1417190414
• NM_000051.4:c.1235+3A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000051.4(ATM):​c.1235+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000248 in 1,613,724 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4
• Conservation: PhyloP100: 5.29
• Publications: 1 publications found

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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108249105-A-G is Pathogenic according to our data. Variant chr11-108249105-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 482570.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.1235+3A>G		splice_region intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.1235+3A>G		splice_region intron	N/A	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.1235+3A>G		splice_region intron	N/A	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.1235+3A>G		splice_region intron	N/A	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.1235+3A>G		splice_region intron	N/A	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251020 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461540 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727090

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111880

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

May 26, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1235+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 8 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was identified in conjunction with another ATM alteration (c.6205C>T, p.Gln2069*) in a patient diagnosed with adult-onset, variant ataxia-telangiectasia (Krenn M et al. Neurol Genet. 2019 Aug;5:e346). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Jan 14, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to G nucleotide substitution at the +3 position of intron 9 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study has detected the out-of-frame skipping of exon 9 in RNA from a heterozygous carrier (PMID: 31403082), although the completeness of the splicing defect was not determined. This variant has been reported in two siblings affected with adult-onset and mild ataxia telangiectasia with an ATM pathogenic covariant, c.6205C>T (p.Gln2069*) (PMID: 31403082). There is no personal and family history of cancer reported in this case study (PMID: 31403082). This variant has been identified in 2/251020 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Ataxia-telangiectasia syndrome Pathogenic:2

Feb 14, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 9 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 altered protein product. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive ataxia-telangiectasia (PMID: 31403082). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 482570). 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 9, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 31403082; internal data). For these reasons, this variant has been classified as Pathogenic.

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

Mar 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Oct 18, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in exon skipping (Krenn et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Observed with a second pathogenic ATM variant (phase unknown) in two siblings with adult-onset ataxia, nystagmus, and dysarthria (Krenn et al., 2019); This variant is associated with the following publications: (PMID: 31403082, Zureick2023[Article])

Familial cancer of breast Uncertain:1

Apr 11, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.80		Position offset: -3

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

Other links and lift over

dbSNP: rs1417190414; hg19: chr11-108119832; COSMIC: COSV99069650;