chr11-108227625-A-G

Variant names:

• chr11-108227625-A-G
• rs730881359
• NM_000051.4:c.1A>G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 8.34

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 94 codons. Genomic position: 108229272. Lost 0.031 part of the original CDS.
• PS1: Another start lost variant in NM_000051.4 (ATM) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108227625-A-G is Pathogenic according to our data. Variant chr11-108227625-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108227625-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.1A>G	p.Met1?	start_lost	Exon 2 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1A>G	p.Met1?	start_lost	Exon 2 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461414 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727046

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 29, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the ATM mRNA. The next in-frame methionine is located at codon 94. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with ataxia-telangiectasia (PMID: 9463314, 12552559, 21665257, 21792198, 22146522, 22649200). ClinVar contains an entry for this variant (Variation ID: 181942). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 04, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the ATM gene, results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This alteration and several others affecting the initiation codon in ATM have been reported in individuals with ovarian cancer, breast cancer, and prostate cancer (Crawford B et al. Breast Cancer Res. Treat., 2017 Jun;163:383-390; Carter NJ et al. Gynecol. Oncol., 2018 12;151(3):481-488; Zafeiriou Z et al. Eur. Urol., 2019 01;75(1):184-192; Decker B at al. J. Med. Genet., 2017 11;54(11):732-741). Initiation codon alterations, including this alteration have also been reported in a compound heterozygous state in multiple patients with ataxia telangiectasia (Gilad S et al. Hum. Mol. Genet., 1996 Apr;5:433-9; Stankovic T et al. Am. J. Hum. Genet., 1998 Feb;62(2):334-45; Buzin CH et al. Hum. Mutat., 2003 Feb;21:123-31; Reiman A et al. Br. J. Cancer, 2011 Aug;105(4):586-91; Byrd PJ et al. Br. J. Cancer, 2012 Jan;106:262-8; Schon et al. Ann. Neurol., 2019 02;85(2):170-180). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

May 22, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the loss of the translation start codon (methionine at codon 1) of the ATM gene. This variant is expected to disrupt the expression of the full-length ATM protein. The next in-frame methionine occurs at codon 94, but it has not been shown if a functional ATM protein product can be produced using p.Met94 as an alternative translation start site. This variant has been reported in trans with p.Gly2891Asp variant in an individual affected with breast cancer and mild ataxia-telangiectasia (PMID: 22146522). Cells derived from this patient showed 10-20% of kinase activity compared to normal cells. A functional study has shown that the cells transfected with this variant construct show a very low level expression of a truncated protein, probably due to the use of a downstream methionine for translation initiation (PMID: 22146522). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different translation initiation codon loss variant (ATM c.2T>C / p.Met1?) is a well documented pathogenic variant (Clinvar variation ID: 187213). Based on the available evidence, this variant is classified as Pathogenic. -

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

May 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

Feb 03, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21665257, 9463314, 21792198, 12552559, 22649200, 22146522, 30549301]. -

Familial pancreatic carcinoma Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.1A>G variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs730881359) as “With Pathogenic, other” allele ,ClinVar (classified as pathogenic by GeneReviews and as likely pathogenic by Counsyl).The variant was not identified in the LOVD 3.0 database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1A>G variant occurs in the first base of the translation initiation site (the methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. The variant was observed in a breast cancer patient with severe reaction to radiotherapy who was found to have 2 ATM mutations: c.1A>G and c.8672G>A (Byrd, 2012). The mutations were found to be on different alleles, and the c.8762G>A allele's resulting mutant protein was expressed and shown to have some residual ATM kinase activity in lymphoblastoid and skin fibroblast cell lines. The c.1A>G variant was hypothesized to ablate the initiation of ATM protein translation entirely but the possibility of the expression of ATM protein if the GUG of the RNA were able to allow translation could not be ruled out. The possibility that initiation from a downstream methionine resulting in a truncated protein was also considered. The c.1A>G mutation was modelled individually by site-directed mutagenesis of full-length normal ATM cDNA. Very low protein levels were observed and the molecular weight was lower that wild type protein, and the kinase level or the resulting protein was too low to be measured in this assay. These observations were consistent with a second patient with a different mutation of the initiation codon. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;T;T;.;T;T;T;T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;.;.;.;.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	-2.3	N;N;D;D;.;N;.;.;.;.;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.;.;.;D;D
Polyphen		0.74, 0.69	.;P;.;.;.;P;P;P;P;P;.
Vest4		0.94, 0.89, 0.96, 0.96
MutPred		0.99		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.91
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881359; hg19: chr11-108098352; COSMIC: COSV53722454; COSMIC: COSV53722454;