chr11-108279501-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000051.4(ATM):​c.3295G>A​(p.Asp1099Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,609,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 3.63
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06612849).
BP6
Variant 11-108279501-G-A is Benign according to our data. Variant chr11-108279501-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188196.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.3295G>A p.Asp1099Asn missense_variant Exon 23 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.3295G>A p.Asp1099Asn missense_variant Exon 23 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000286
AC:
7
AN:
244464
Hom.:
0
AF XY:
0.0000378
AC XY:
5
AN XY:
132216
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:
0.000199
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000199
AC:
29
AN:
1457008
Hom.:
0
Cov.:
30
AF XY:
0.0000290
AC XY:
21
AN XY:
724648
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:
0.000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.000867
AC:
3
AN:
3476

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:3
Nov 03, 2024
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3295G>A (p.Asp1099Asn) sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1099 of the ATM protein (p.Asp1099Asn). This variant is present in population databases (rs372966951, gnomAD 0.02%). This missense change has been observed in individuals with breast, colorectal, and other cancers (PMID: 19781682, 28135145, 30455982, 30093976); This variant is associated with the following publications: (PMID: 21787400, 26787654, 19781682, 25231023, 12697903, 28135145, 30455982, 30093976, 26976419) . ClinVar contains an entry for this variant (Variation ID: 188196).In silico analysis supports that this missense variant does not alter protein structure/function. 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. -

Oct 10, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 22, 2023
Neuberg Centre For Genomic Medicine, NCGM
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The observed missense variant c.3295G>A(p.Asp1099Asn) in ATM gene has been reported previously in multiple individuals with various cancers (Yurgelun MB, et al., 2017, Howitt BE, et al., 2015). This variant is reported with 0.003% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Likely Beningn/ Uncertain Significance (multiple submissions).The amino acid Asp at position 1099 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Asp1099Asn in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Uncertain Significance. -

Ataxia-telangiectasia syndrome Uncertain:2
Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1099 of the ATM protein (p.Asp1099Asn). This variant is present in population databases (rs372966951, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 19781682, 21787400, 28135145, 30093976). ClinVar contains an entry for this variant (Variation ID: 188196). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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. -

Sep 16, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
Oct 31, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 29, 2024
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. -

not specified Uncertain:1
Sep 30, 2021
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: ATM c.3295G>A (p.Asp1099Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249262 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3295G>A has been reported in the literature in individuals affected with Breast Cancer, Lymphoma, Mullerian Adenocarcinoma, Colorectal cancer and Pediatric cancer predisposition syndrome without evidence for causality (example, Fang_2003, Tavtigian_2009, Goldgar_2011, Howitt_2015, Yurgelun_2017, Tung_2016, Young_2015, Chan_Oncotarget_2018, Chan_Genomic Med_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory has classified the variant as likely benign and four others have classified it as variant of unknown significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

ATM-related disorder Uncertain:1
May 30, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The ATM c.3295G>A variant is predicted to result in the amino acid substitution p.Asp1099Asn. This variant has been reported in patients with breast or colorectal cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table S2, Chan et al. 2018. PubMed ID: 30093976). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD and is listed in ClinVar with conflicting interpretation of likely benign (1) and uncertain (7) (https://www.ncbi.nlm.nih.gov/clinvar/variation/188196/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1
Oct 26, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, colorectal, and other cancers (PMID: 19781682, 28135145, 30455982, 30093976); This variant is associated with the following publications: (PMID: 21787400, 26787654, 19781682, 25231023, 12697903, 28135145, 30455982, 30093976, 26976419) -

Malignant tumor of breast Uncertain:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The ATM p.Asp1099Asn variant was identified in 4 of 15480 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and colorectal cancer and was not identified in 7694 control chromosomes from healthy individuals (Tavtigian 2009, Goldgar 2011, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs372966951) as "With Uncertain significance allele", and in ClinVar (as uncertain significance by Ambry Genetics, Invitae, GeneDx, and Integrated Genetics). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 7 of 239322 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5374 chromosomes (freq: 0.0002), and South Asian in 6 of 30298 chromosomes (freq: 0.0002); it was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Asp1099 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
19
DANN
Benign
0.96
DEOGEN2
Benign
0.055
.;T;T
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.25
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.71
T;T;.
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.066
T;T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.5
.;M;M
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.83
N;N;N
REVEL
Benign
0.072
Sift
Benign
0.35
T;T;T
Sift4G
Benign
0.25
T;T;T
Polyphen
0.0020
.;B;B
Vest4
0.34, 0.27
MutPred
0.22
Gain of MoRF binding (P = 0.0307);Gain of MoRF binding (P = 0.0307);Gain of MoRF binding (P = 0.0307);
MVP
0.75
MPC
0.12
ClinPred
0.079
T
GERP RS
2.8
Varity_R
0.027
gMVP
0.15

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

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

Other links and lift over

dbSNP: rs372966951; hg19: chr11-108150228; COSMIC: COSV105845657; API