rs778031266

chr11-108316114-G-Achr11-108316114-G-Cchr11-108316114-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):c.6198+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ATM NM_000051.4 splice_donor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.22

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 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.011122015 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.1, offset of 21, new splice context is: ttgGTaaag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• 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 11-108316114-G-A is Pathogenic according to our data. Variant chr11-108316114-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 221911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.6198+1G>A		splice_donor_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.6198+1G>A		splice_donor_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251016 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135668

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461348 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727018

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.000106 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2022	Variant summary: ATM c.6198+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251016 control chromosomes. c.6198+1G>A has been reported in the literature in individuals affected with Ataxia-Telangiectasia, multiple primary tumor, or breast cancer (e.g. Stankovic_1998, Whitworth_2018, Schon_2019, Dorling_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 06, 2023	This sequence change affects a donor splice site in intron 42 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs778031266, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with ataxia telangiectasia. In addition, it has been reported as heterozygous in individuals affected with ATM-related cancers (PMID: 9463314, 16832357, 21459046, 21792198, 26220245, 26915675, 29909963, 30549301). This variant is also known as IVS44+1G>A. ClinVar contains an entry for this variant (Variation ID: 221911). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 19, 2023	The c.6198+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 41 of the ATM gene. This mutation was detected in two ataxia-telangiectasia (AT) patients, although a second pathogenic ATM mutation was not detected in either individual (Stankovic T et al, Am. J. Hum. Genet. 1998 Feb; 62(2):334-45; Reiman A, Br. J. Cancer 2011 Aug; 105(4):586-91). However, this mutation was subsequently identified with a second ATM mutation in a 22-year-old patient with AT, although phase was not confirmed (Schon K et al. Ann. Neurol., 2019 02;85:170-180). In addition, this mutation was identified in a breast cancer family (Renwick A, Nat. Genet. 2006 Aug; 38(8):873-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Furthermore, 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; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2022	This variant causes a G to A nucleotide substitution at the +1 position of intron 42 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual with a family history and/or affected with hereditary breast and ovarian cancer (PMID: 26898890). This variant has also been reported in multiple individuals with ataxia-telangiectasia, with at least one case confirmed in trans with a known pathogenic mutation in ATM (PMID: 9463314, 21459046, 21792198, 30549301, 33547824). This variant has been identified in 1/251016 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. -
Likely pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 24, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 29, 2024	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Abnormal central motor function Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2022

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Identified in the homozygous state or with a second ATM variant in individuals with ataxia telangiectasia or other ATM-related disorders, including patients exhibiting reduced ATM protein and kinase activity (Stankovic 1998, Exley 2011, Reiman 2011, Al-Mousa 2016, Schon 2019, Amirifar 2021); Observed in the heterozygous state in individuals with breast and other cancers (Renwick 2006, Caminsky 2016, Whitworth 2018, Dorling 2021); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS44+1G>A; This variant is associated with the following publications: (PMID: 9463314, 21459046, 26898890, 21792198, 33471991, 33547824, 26915675, 16832357, 29909963, 30549301, 26220245) -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Dr. Peter K. Rogan Lab, Western University

Dec 22, 2015

Sequenced patient with familial breast cancer -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		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: rs778031266; hg19: chr11-108186841; COSMIC: COSV53751894; COSMIC: COSV53751894;