11-108272591-T-C

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.3137T>C(p.Leu1046Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,832 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1046F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9 U:2
• Conservation: PhyloP100: 6.23

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 11-108272591-T-C is Pathogenic according to our data. Variant chr11-108272591-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186558.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-108272591-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.3137T>C	p.Leu1046Pro	missense_variant	21/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.3137T>C	p.Leu1046Pro	missense_variant	21/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461494 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727066

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74500

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1046 of the ATM protein (p.Leu1046Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 27664052; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 186558). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters ATM gene expression (PMID: 27664052). This variant disrupts the p.Leu1046 amino acid residue in ATM. Other variant(s) that disrupt this residue have been observed in individuals with ATM-related conditions (PMID: 19535770), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 26, 2017	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ATM: PM3:Strong, PM2, PS3:Supporting, BP1 -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 19, 2023	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 16, 2022	The ATM c.3137T>C (p.Leu1046Pro) variant is absent in GnomAD v2.1.1 (PM2_Supporting). In silico protein predictors (REVEL Impact: 0.854; Align-GVGD: C65) predict that this alteration is deleterious (PP3). This variant has also been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals with ataxia-telangiectasia (PMIDs: 27664052, 31429931) (PM3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 21, 2024	The p.L1046P variant (also known as c.3137T>C), located in coding exon 20 of the ATM gene, results from a T to C substitution at nucleotide position 3137. The leucine at codon 1046 is replaced by proline, an amino acid with similar properties. This alteration has been detected in a homozygous state in a patient with consistent features of ataxia telangiectasia (A-T), as well as in a compound heterozygous state with a frameshift mutation in a patient with a clinical diagnosis of A-T (Shakya S et al. Clin Genet, 2019 12;96:566-574; Carranza D et al. Neuromolecular Med, 2017 Mar;19:161-174). In addition, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2023	This missense variant replaces leucine with proline at codon 1046 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In a large international case-control meta-analysis, this variant was reported in 1/60465 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant was reported in the homozygous state in an individual with clinical features of ataxia-telangiectasia (PMID: 31429931). This variant has also been reported in the compound heterozygous state with a pathogenic truncation variant, c.640del (p.Ser214Profs*16), in an individual affected with ataxia-telangiectasia (PMID: 27664052). Cells derived from this individual showed no detectable protein expression and increased radiosensitivity compared to controls (PMID: 27664052). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;D;.
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.10	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.98	.;D;D
Vest4		0.76, 0.77
MutPred		0.80		Loss of helix (P = 0.0072);Loss of helix (P = 0.0072);Loss of helix (P = 0.0072);
MVP		0.98
MPC		0.65
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.76
gMVP		0.78

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: rs568461905; hg19: chr11-108143318;