11-108252858-T-C

Variant names:

• chr11-108252858-T-C
• rs786203783
• NM_000051.4:c.1844T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000051.4(ATM):​c.1844T>C​(p.Leu615Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,860 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: 0.0000027 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 6.30

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 11-108252858-T-C is Pathogenic according to our data. Variant chr11-108252858-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187501.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.1844T>C	p.Leu615Pro	missense_variant	Exon 12 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1844T>C	p.Leu615Pro	missense_variant	Exon 12 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460860 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726776

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2 Uncertain:1

Feb 20, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2021

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed in trans with a pathogenic variant [NM_000051.3:c.8687A>C (p.Gln2896Pro)] as compound heterozygous (3billion dataset, PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.792, PP3). Patient's phenotype is considered compatible with Ataxia-telangiectasia (3billion dataset, PP4). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline -

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 615 of the ATM protein (p.Leu615Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or prostate cancer (PMID: 29368341, 30549301, 32901917; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 187501). 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. 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. -

Familial cancer of breast Pathogenic:2

Aug 30, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.1844T>C (p.Leu615Pro) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been observed in trans with a pathogenic variant [NM_000051.3:c.8687A>C (p.Gln2896Pro)] in at least one patient with ataxia telangiectasia (PMID: 26896183, 30549301, 32901917). ATM expression and ATM activity assays performed on a lymphoblastoid cell line derived from the patient’s blood demonstrated residual kinase activity. In addition, the in silico tool REVEL predicts a deleterious effect on protein function. This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). In summary, this variant meets criteria to be classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L615P variant (also known as c.1844T>C), located in coding exon 11 of the ATM gene, results from a T to C substitution at nucleotide position 1844. The leucine at codon 615 is replaced by proline, an amino acid with similar properties. This variant was identified in conjunction with other pathogenic variants in ATM in multiple individuals diagnosed with ataxia-telangiectasia (Schon K et al. Ann Neurol 2019 02;85(2):170-180; Seo GH et al. Clin Genet 2020 12;98(6):562-570). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Feb 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 615 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). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in the compound heterozygous state in an individual affected with autosomal recessive variant ataxia-telangiectasia (PMID: 26896183, 30549301), indicating that this variant contributes to disease. This variant has been reported in trans with a variant of uncertain significance, c.8687A>C (p.Gln2896Pro), in a second individual affected with ataxia-telangiectasia (PMID: 32901917). In addition, this variant has been observed in individuals affected with prostate cancer (PMID: 29368341). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Pathogenic:1

Jan 03, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in an individual with prostate cancer (PMID: 29368341); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32901917, 30549301, 29368341, 26896183) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	.;D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.8	.;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.98	.;D;D
Vest4		0.99, 0.98
MutPred		0.76		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.96
MPC		0.74
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.90
gMVP		0.89

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: rs786203783; hg19: chr11-108123585;