11-108330261-T-C

Position:

• chr11-108330261-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000051.4(ATM):​c.7355T>C​(p.Leu2452Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,842 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 7.56

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATM (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a mutagenesis_site Loss of phosphorylation of target proteins. (size 0) in uniprot entity ATM_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 11-108330261-T-C is Pathogenic according to our data. Variant chr11-108330261-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 481101.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.7355T>C	p.Leu2452Pro	missense_variant	50/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7355T>C	p.Leu2452Pro	missense_variant	50/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2024	The p.L2452P variant (also known as c.7355T>C), located in coding exon 49 of the ATM gene, results from a T to C substitution at nucleotide position 7355. The leucine at codon 2452 is replaced by proline, an amino acid with similar properties. This alteration was identified in a patient with ataxia telangiectasia in conjunction with another ATM alteration, c.7638_7646del9 (Jackson TJ et al. Dev Med Child Neurol. 2016 07;58:690-7). In a functional study, this alteration showed loss of kinase activity (Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). This alteration has also been identified in 1 of 2570 Caucasian breast cancer cases and 0 of 1448 controls (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73). This amino acid position is 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 23, 2023	This missense variant replaces leucine with proline at codon 2452 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). Functional studies have shown that this variant disrupted kinase activity (PMID: 19431188, 26896183). This variant has been observed in two individuals affected with autosomal recessive ataxia-telangiectasia, one of which was confirmed in the compound heterozygous state with a second pathogenic variant, indicating that this variant contributes to disease (PMID: 19431188, 26896183). This variant was also detected in a breast cancer case-control analysis (PMID: 21787400). 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 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 07, 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. Experimental studies have shown that this missense change affects ATM function (PMID: 19431188). 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: 481101). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 19431188, 26896183). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2452 of the ATM protein (p.Leu2452Pro). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 13, 2022

Variant summary: ATM c.7355T>C (p.Leu2452Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251270 control chromosomes (gnomAD). c.7355T>C has been reported in the literature as a compound heterozygous genotype in at least one individual affected with Ataxia-Telangiectasia and has been found in at least one individual undergoing ATM sequencing for breast cancer risk (e.g. Barone_2009, Jackson_2016, Goldgar_2011). These report(s) do not provide unequivocal conclusions about association of the variant with disease. At least one publication reports experimental evidence evaluating an impact on protein function. It was found that the variant ATM protein had little to no detectable kinase activity toward downstream targets in an expression model system (e.g. Barone_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T;.
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.79		Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);
MVP		0.99
MPC		0.74
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.79

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: rs1555123032; hg19: chr11-108200988; COSMIC: COSV53744079; COSMIC: COSV53744079;