Variant 11-108271312-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):c.2983C>T(p.Leu995Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.55

Variant links:

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 links:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.2983C>T	p.Leu995Phe	missense_variant	20/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.2983C>T	p.Leu995Phe	missense_variant	20/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151480

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151480

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73886

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 21, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 995 of the ATM protein (p.Leu995Phe). 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: 127365). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2013

This variant is denoted ATM c.2983C>T at the cDNA level, p.Leu995Phe (L995F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT) in exon 20. This variant has not, to our knowledge, been published in the literature as either a mutation or a benign polymorphism. Furthremore, ATM Leu995Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Variant Server, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is well conserved throughout evolution but is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on the currently available information, we cannot assess whether Leu995Phe is a pathogenic mutation or a benign variant. This variant has been seen apparently mosaic. The variant is found in BR-OV-HEREDIC panel(s). -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The p.L995F variant (also known as c.2983C>T), located in coding exon 19 of the ATM gene, results from a C to T substitution at nucleotide position 2983. The leucine at codon 995 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. 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. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

.;T;T

Eigen

Benign

-0.013

Eigen_PC

Benign

-0.026

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.75

T;T;.

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.7

.;M;M

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.031

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.68

.;P;P

Vest4

0.45, 0.46

MutPred

0.27

Gain of methylation at K999 (P = 0.1079);Gain of methylation at K999 (P = 0.1079);Gain of methylation at K999 (P = 0.1079);

MVP

0.96

MPC

0.32

ClinPred

0.84

GERP RS

2.5

Varity_R

0.15

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.48

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.48

Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over