11-108294934-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000051.4(ATM):​c.4784A>G​(p.Asn1595Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 4.79
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.41367325).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.4784A>G p.Asn1595Ser missense_variant Exon 32 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.4784A>G p.Asn1595Ser missense_variant Exon 32 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251242
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135786
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461492
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727070
show subpopulations
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:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3
May 14, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces asparagine with serine at codon 1595 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 been reported in individuals affected with breast cancer in the literature (PMID: 20305132, 31159747). This variant has been identified in 1/251242 chromosomes 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. -

Aug 01, 2018
GeneKor MSA
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 27, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.N1595S variant (also known as c.4784A>G), located in coding exon 31 of the ATM gene, results from an A to G substitution at nucleotide position 4784. The asparagine at codon 1595 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported as a variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing multigene panel testing for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer 2019 Jun;19(1):535). This alteration was also identified in 1/2105 women with invasive breast cancer who were tested for variants in the ATM gene (Bernstein JL et al. J Natl Cancer Inst 2010 Apr;102(7):475-83). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:2
May 24, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with contralateral breast cancer and absent in controls (Bernstein et al., 2010); This variant is associated with the following publications: (PMID: 31159747, 20305132) -

Sep 26, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The ATM c.4784A>G (p.Asn1595Ser) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and polar Asparagine (N) with a small size and polar Serine (S) located outside of known functional domains (InterPro, Pfam). 3/3 in silico tools predict a benign outcome for this substitution (SNPs&GO and Mutation taster not captured due to low reliability index). This variant was found in 1/121324 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). To our knowledge, the variant has not been reported in affected patients with strong evidence for causality and studies assessing the impact the variant may have on the function of ATM protein have not been published at the time of classification either. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS. -

Ataxia-telangiectasia syndrome Uncertain:1Benign:1
Jan 28, 2021
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1
Mar 13, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.082
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.080
T;T
Eigen
Benign
0.011
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.92
D;.
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.41
T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Uncertain
2.1
M;M
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.12
Sift
Benign
0.21
T;T
Sift4G
Benign
0.22
T;T
Polyphen
0.0050
B;B
Vest4
0.59
MutPred
0.47
Gain of phosphorylation at N1595 (P = 0.1265);Gain of phosphorylation at N1595 (P = 0.1265);
MVP
0.82
MPC
0.099
ClinPred
0.32
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.23
gMVP
0.11

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

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

Other links and lift over

dbSNP: rs777812804; hg19: chr11-108165661; API