rs587780639

Positions:

• chr11-108332037-G-A
• chr11-108332037-G-C
• chr11-108332037-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.7788G>A​(p.Glu2596=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000205 in 1,461,294 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 6.76

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

Verdict is Pathogenic. Variant got 14 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 11-108332037-G-A is Pathogenic according to our data. Variant chr11-108332037-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 135778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108332037-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7788G>A	p.Glu2596=	splice_region_variant, synonymous_variant	52/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7788G>A	p.Glu2596=	splice_region_variant, synonymous_variant	52/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250802 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135562

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461294 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726930

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 19, 2023	This sequence change affects codon 2596 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587780639, gnomAD 0.002%). This variant has been observed in individuals with ataxia telangiectasia (PMID: 9792409, 26693373). ClinVar contains an entry for this variant (Variation ID: 135778). 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 52, also known as exon 54, but is expected to preserve the integrity of the reading-frame (PMID: 9792409; Invitae). For these reasons, this variant has been classified as Pathogenic. -
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%). Synonymous variant leading to alternate splicing. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23532176 , 25460276 , 9792409). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.81). 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: 26693373 , 9792409). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000135778 / PMID: 26681312). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 10, 2017	- -

Familial cancer of breast Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 01, 2024	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9792409, 26693373, 21665257, 33551102, 33547824]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 10, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2019	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site, resulting in an in-frame deletion of exon 52, also known as exon 54 by alternate numbering, which has been confirmed with protein truncation testing (Broeks 1998); Observed with a pathogenic variant on the opposite allele (in trans) or in the homozygous state in unrelated patients with ataxia telangiectasia in the published literature (Broeks 1998, Aygun 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 9792409, 25525159, 26681312, 26693373, 28126470, 32283892) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ATM: PS3, PM2, PS4:Moderate, PP3 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 19, 2022	This synonymous variant does not change the encoded amino acid at codon 2596 of the ATM protein but it causes a G to A substitution at the last nucleotide of exon 52 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant causes in-frame skipping of exon 52 (also known as exon 54 in the literature) which encodes part of the FAT domain (PMID: 9792409, 35716007). This variant has been reported in the homozygous state or compound heterozygous state in multiple individuals affected with ataxia-telangiectasia (PMID: 9792409, 26693373, 33547824, 33551102). This variant has also been reported in an individual affected with colorectal cancer (PMID: 32283892). This variant has been identified in 1/250802 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 Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2023	The c.7788G>A pathogenic mutation (also known as p.E2596E), located in coding exon 51 of the ATM gene, results from a G to A substitution at nucleotide position 7788. This nucleotide substitution does not change the glutamic acid at codon 2596. However, this change occurs in the last base pair of coding exon 51, which makes it likely to have some effect on normal mRNA splicing. This mutation has been reported in multiple individuals with a clinical diagnosis of ataxia telangiectasia, two of whom were reported to be homozygous for the mutation (Broeks A et al. Hum. Mutat. 1998;12:330-7; Aygün FD et al. Case Rep Pediatr. 2015;2015: 615368). 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. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 26, 2020

Variant summary: ATM c.7788G>A (p.Glu2596Glu) 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: Two predict the variant abolishes a 5 splicing donor site. One predicts the variant weakens a 5 donor site. The variant allele was found at a frequency of 4e-06 in 250802 control chromosomes (gnomAD). c.7788G>A has been reported in the literature in multiple individuals affected with ataxia-telangiectasia or ovarian cancer (Broeks_1998, Micol_2011, Aygun_2015, Arvai_2019). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in shortening ATM protein (skipping of exon 52) (Broeks_1998) and expected to result in in-frame deletion of the protein, comprising a large part of FAT domain involved in stability of the protein (Micol_2011, PMID: 23532176). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780639; hg19: chr11-108202764;