11-108267243-A-T

Variant names:

• chr11-108267243-A-T
• rs587779823
• NM_000051.4:c.2539A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000051.4(ATM):​c.2539A>T​(p.Met847Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. M847V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.69
• Publications: 3 publications found

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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15538603).
• BP6: Variant 11-108267243-A-T is Benign according to our data. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957. Variant chr11-108267243-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 231957.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2539A>T	p.Met847Leu	missense_variant	Exon 17 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2539A>T	p.Met847Leu	missense_variant	Exon 17 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Dec 18, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Sep 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with leucine at codon 847 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. 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. -

Ataxia-telangiectasia syndrome Uncertain:1

Jul 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 847 of the ATM protein (p.Met847Leu). 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: 231957). 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 tolerated. 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. -

not provided Uncertain:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.085	.;T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.46	T;T;.
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	.;M;M
PhyloP100		3.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.089
Sift	Benign	0.036	D;D;D
Sift4G	Uncertain	0.044	D;T;T
Polyphen		0.011	.;B;B
Vest4		0.39, 0.43
MutPred		0.28		Loss of catalytic residue at M847 (P = 0.0082);Loss of catalytic residue at M847 (P = 0.0082);Loss of catalytic residue at M847 (P = 0.0082);
MVP		0.83
MPC		0.12
ClinPred		0.14	T
GERP RS		1.5
Varity_R		0.12
gMVP		0.19
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs587779823; hg19: chr11-108137970;