11-108309110-A-G

Variant names:

• chr11-108309110-A-G
• rs774925473
• NM_000051.4:c.5763-1050A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1_Strong PVS1_Strong PM3

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:19 O:1
• Conservation: PhyloP100: 0.274
• Publications: 11 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]

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]

ACMG classification

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.5763-1050A>G		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.5763-1050A>G		intron	N/A	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-39T>C		intron	N/A	NP_001317297.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.5763-1050A>G		intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.5763-1050A>G		intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*827-1050A>G		intron	N/A	ENSP00000435747.2	E9PIN0

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

GnomAD2 exomes AF: 0.0000236 AC: 3 AN: 127224 AF XY: 0.0000287

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: 0.0000637

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

African (AFR) AF: 0.0000410 AC: 1 AN: 24368

American (AMR) AF: 0.00 AC: 0 AN: 35086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22802

East Asian (EAS) AF: 0.00 AC: 0 AN: 33826

South Asian (SAS) AF: 0.00 AC: 0 AN: 71162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4676

European-Non Finnish (NFE) AF: 0.000113 AC: 84 AN: 740552

Other (OTH) AF: 0.0000879 AC: 4 AN: 45524

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15286

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: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68034

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

Alfa AF: 0.0000533 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Ataxia-telangiectasia syndrome (6)
4	-	-	not provided (4)
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Ataxia - telangiectasia variant (1)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
1	-	-	ATM-related cancer predisposition (1)
1	-	-	ATM-related disorder (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Familial colorectal cancer type X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	18
DANN	Benign	0.58
PhyloP100		0.27
Mutation Taster		=99/1	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs774925473; hg19: chr11-108179837;