chr11-108317377-T-C

Position:

• chr11-108317377-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.6203T>C​(p.Leu2068Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,066 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2068F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 7.27

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 11-108317377-T-C is Pathogenic according to our data. Variant chr11-108317377-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 489568.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=2}. Variant chr11-108317377-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.6203T>C	p.Leu2068Ser	missense_variant	43/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.6203T>C	p.Leu2068Ser	missense_variant	43/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459066 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725916

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 27, 2024	The p.L2068S variant (also known as c.6203T>C), located in coding exon 42 of the ATM gene, results from a T to C substitution at nucleotide position 6203. The leucine at codon 2068 is replaced by serine, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of ataxia telangiectasia (Anheim M et al. Neurogenetics, 2010 Feb;11:1-12; Jacquemin V et al. Eur J Hum Genet, 2012 Mar;20:305-12; Carranza D et al. Neuromolecular Med, 2017 Mar;19:161-174; Berland A et al. J Allergy Clin Immunol, 2019 Jan;143:325-334.e2). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Jun 30, 2021	This missense variant replaces leucine with serine at codon 2068 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported in the compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 19440741, 27664052). Cells derived from one of these individuals have shown decreased ATM protein expression, no detectable ATM kinase activity, and some radiosensitivity (PMID: 27664052). This variant has also been reported in the homozygous state in an individual affected with atypical ataxia-telangiectasia (PMID: 22071889, 31050087). Cells derived from this individual have shown a slight decrease in ATM protein expression and residual ATM kinase activity, suggesting that the variant is hypomorphic (PMID: 22071889, 31050087). This variant has been reported in individuals affected with breast cancer (PMID: 30303537). 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. It is however important to note that this variant may be hypomorphic and the associated cancer risk may be different from that of other pathogenic ATM variants. Medical management should be considered based on the individual’s personal and family history. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c. 6203T>C (p.Leu2068Ser) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). The variant was detected in three ataxia telangiectasia probands: two compound heterozygotes with truncating variants and one homozygote (PS4_Moderate; PMID: 19440741; PMID: 27664052; PMID: 22071889). Studies in ataxia-telangiectasia patient carrier cells show trace or low levels of ATM protein, no autophosphorilation in Serine 1981 and no (or trace) phosphorylation of two substrates (H2AX Ser139 and KAP1 Ser824) upon irradiation and intermediate irradiation sensitivity in a colony survival assay (PS3_Moderate; PMID: 19440741; PMID: 27664052). Therefore, this variant meets criteria to be classified as likely pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PS4_Moderate + PS3_Moderate + PP3 (PMID: 33280026). -

Ataxia-telangiectasia syndrome Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 09, 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 22071889, 27664052, 31050087). 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: 489568). This missense change has been observed in individual(s) with ataxia-telangiectasia, late-onset ataxia, or breast cancer and ataxia-telangiectasia (PMID: 19440741, 22071889, 27664052, 30303537). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2068 of the ATM protein (p.Leu2068Ser). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2023	Variant summary: ATM c.6203T>C (p.Leu2068Ser) results in a non-conservative amino acid change located in the PIK-related kinase (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251316 control chromosomes. c.6203T>C has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Anheim_2010, Carranza_2017, Jacquemin_2012) and Breast cancer (Girard_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function showing an impact on protein function (Jacquemin_2012). The following publications have been ascertained in the context of this evaluation (PMID: 19440741, 27664052, 30303537, 22071889). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely pathogenic (n=4) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 03, 2019	The ATM c.6203T>C (p.Leu2068Ser) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two individuals with ataxia-telangiectasia (Anheim et al. 2010; Carranza et al. 2017). Control data are unavailable for this variant. The p.Leu2068Ser variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the evidence, the p.Leu2068Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for ataxia-telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 13, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22071889, 29906526, 19440741, 27664052]. Functional studies indicate this variant impacts protein function [PMID: 22071889, 31050087, 27664052]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;.
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.78		Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);
MVP		0.98
MPC		0.53
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.44
gMVP		0.86

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: rs1555114558; hg19: chr11-108188104;