11-108281168-G-T

Position:

• chr11-108281168-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.3576G>T​(p.Lys1192Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K1192K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.97

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108281168-G-T is Pathogenic according to our data. Variant chr11-108281168-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 490539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.3576G>T	p.Lys1192Asn	missense_variant, splice_region_variant	24/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3576G>T	p.Lys1192Asn	missense_variant, splice_region_variant	24/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2022	The c.3576G>T variant (also known as p.K1192N), located in coding exon 23 of the ATM gene, results from a G to T substitution at nucleotide position 3576. The amino acid change results in lysine to asparagine at codon 1192, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 23, which makes it likely to have some effect on normal mRNA splicing. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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	Aug 04, 2021	This variant causes a G to T nucleotide substitution at the last nucleotide of exon 24 of the ATM gene and replaces lysine with asparagine at codon 1192 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study has reported that this variant leads to the skipping of exon 24 in the RNA transcript, which is expected to result in an in-frame deletion of 58 amino acids of the ATM protein (communication with an external laboratory). Moreover, RNA studies have reported that a different variant affecting the same nucleotide position, c.3576G>A, also caused abnormal RNA splicing (PMID: 9887333, 21965147). While to our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature, the similar variant, c.3576G>A, has been reported in individuals affected with ataxia-telangiectasia and breast cancer and is considered to be disease-causing (ClinVar variation ID: 3035). It suggests that this nucleotide position is clinically significant. 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. -

Ataxia-telangiectasia syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1192 of the ATM protein (p.Lys1192Asn). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant has not been reported in the literature in individuals affected with ATM-related conditions. 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. This variant disrupts the c.3576G nucleotide in the ATM gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8845835, 9887333, 17124347, 19691550, 22071889). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 24, also known as exon 23, but is expected to preserve the integrity of the reading-frame (external communication). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 490539). -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 22, 2024

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9887333]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8698354, Myriad internal data]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	.;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.8	.;M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.71, 0.77
MutPred		0.34		Loss of methylation at K1192 (P = 0.0184);Loss of methylation at K1192 (P = 0.0184);Loss of methylation at K1192 (P = 0.0184);
MVP		0.96
MPC		0.61
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.75
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776551; hg19: chr11-108151895;