11-108227695-A-T

Position:

• chr11-108227695-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):​c.71A>T​(p.Lys24Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.89

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]

ATM (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.71A>T	p.Lys24Met	missense_variant, splice_region_variant	2/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.71A>T	p.Lys24Met	missense_variant, splice_region_variant	2/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 14, 2021	The p.K24M variant (also known as c.71A>T), located in coding exon 1 of the ATM gene, results from an A to T substitution at nucleotide position 71. The lysine at codon 24 is replaced by methionine, an amino acid with similar properties. This nucleotide position is poorly 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 an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 06, 2019	- -

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 407733). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 24 of the ATM protein (p.Lys24Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;T;T;.;T;T;T;T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;.;.;.;.;.;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.8	.;L;.;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.8	D;N;D;D;.;N;.;.;.;.;.
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;D;D;D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;.;.;.;D;D
Polyphen		0.99, 0.92	.;D;.;.;.;D;P;P;P;P;.
Vest4		0.28, 0.27, 0.26, 0.36
MutPred		0.22		Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);Loss of methylation at K24 (P = 0.0228);
MVP		0.83
MPC		0.54
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.67		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: rs1060501710; hg19: chr11-108098422;