chr11-108281168-G-C

Position:

• chr11-108281168-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000051.4(ATM):​c.3576G>C​(p.Lys1192Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,228 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K1192K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108281168-G-C is Pathogenic according to our data. Variant chr11-108281168-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1732830.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461228 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726966

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

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). This variant also falls at the last nucleotide of exon 24, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 1732830). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, 19691550, 22071889, 27599564). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2022

The p.K1192N variant (also known as c.3576G>C), located in coding exon 23 of the ATM gene, results from a G to C 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. Another alteration impacting the same nucleotide position (c.3576G>A) has been described in individuals with a clinical diagnosis of ataxia telangiectasia, and has been observed in the homozygous state in individuals with severe disease (Telatar M et al. Am J Hum Genet, 1998 Jan;62:86-97; Gilad S et al. Am J Hum Genet, 1998 Mar;62:551-61; Sandoval N et al. Hum Mol Genet, 1999 Jan;8:69-79). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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	0.099	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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-108151895;