rs730881359

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-108227625-A-C
• chr11-108227625-A-G
• chr11-108227625-A-T

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>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ATM NM_000051.4 initiator_codon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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-C is Pathogenic according to our data. Variant chr11-108227625-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.1A>C	p.Met1?	initiator_codon_variant	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>C	p.Met1?	initiator_codon_variant	Exon 2 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Jan 05, 2025

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, 21792198, 22649200). ClinVar contains an entry for this variant (Variation ID: 187213). For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This start codon mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory in trans with a pathogenic missense mutation in a 3-year-old male with hypotonia, ataxic gait, short stature, dysmorphic features. -

Jan 20, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ATM c.1A>C (p.Met1Leu) variant involves the alteration of a conserved nucleotide causing a substitution of initiation codon in exon 2 and is located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) (InterPro). 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Since this variant affects the initiation codon, it is expected to alter the translation of ATM protein. Two other substitution variants in the initiation codon (p.Met1Ile and p.Met1Thr) have been classified as likely pathogenic/pathogenic by our laboratory. This variant is absent in 215414 control chromosomes in gnomAD. One clinical diagnostic laboratory has classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 19, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>C), located in coding exon 1 of the ATM gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This mutation was identified in 1/1207 cases of BRCA1/2-negative French women diagnosed with breast cancer who had a sister with breast cancer and in 0/1199 general population controls (Girard E et al. Int J Cancer. 2019 04;144(8):1962-74). Two other disease-causing mutations at the initiation codon, c.3G>A and c.2T>C, have been reported in a compound heterozygous state in patients with Ataxia Telangectasia (AT) (Gilad S, Hum. Mol. Genet. 1996 Apr; 5(4):433-9. Buzin CH, Hum. Mutat. 2003 Feb; 21(2):123-31). Another alteration at the initiation codon, c.1A>G, has been identified in trans with an additional ATM alteration in a patient with very mild AT symptoms. Functional analysis of the two alterations independently revealed that the c.1A>G allele produced very low protein levels, and the protein that was produced was of a lower molecular weight than wild type ATM suggesting initiation at a downstream methionine resulting in a premature truncation codon (Byrd PJ, Br. J. Cancer 2012 Jan; 106(2):262-8). This amino acid position is highly conserved in available vertebrate species. 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. -

Jul 26, 2024

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 translation initiation methionine codon 1 of the ATM protein. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in trans with a pathogenic missense mutation in a child affected with hypotonia, ataxic gait, short stature, and dysmorphic features (Clinvar variation ID: 187213 and SCV000807215.1) and in an individual affected with early-onset breast cancer (Color internal data). 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. -

Familial cancer of breast Pathogenic:1

Jan 10, 2024

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]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.21	.;T;T;T;.;T;T;T;T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;.;.;.;.;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-1.8	N;N;N;N;.;N;.;.;.;.;.
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D;D;D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.;.;.;D;D
Polyphen		0.55, 0.014	.;P;.;.;.;P;B;B;B;B;.
Vest4		0.90, 0.81, 0.85, 0.89
MutPred		0.98		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.90
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;