11-108325341-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000051.4(ATM):​c.6604T>G​(p.Tyr2202Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,610,648 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: 𝑓 0.000027 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

6
8
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:1

Conservation

PhyloP100: 7.21
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]
C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.6604T>G p.Tyr2202Asp missense_variant Exon 46 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.6604T>G p.Tyr2202Asp missense_variant Exon 46 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.0000266
AC:
4
AN:
150444
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000244
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:
0.0000443
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
251042
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135710
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000562
AC:
82
AN:
1460204
Hom.:
0
Cov.:
32
AF XY:
0.0000523
AC XY:
38
AN XY:
726444
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:
0.0000729
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000266
AC:
4
AN:
150444
Hom.:
0
Cov.:
30
AF XY:
0.0000136
AC XY:
1
AN XY:
73388
show subpopulations
Gnomad4 AFR
AF:
0.0000244
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:
0.0000443
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000491
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:12Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:3
Oct 06, 2016
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 23, 2018
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.6604T>G (p.Tyr2202Asp) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 121096 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (1.7e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.6604T>G, has been reported in the literature in individuals affected with chronic lymphocytic leukemia and head and neck squamous cell carcinoma (Mansouri 2014, Lu 2015), however it also was found in women, older than age 70 years who have never had cancer (in the FLOSSIES database). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Ataxia-telangiectasia syndrome Uncertain:2
Mar 19, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2202 of the ATM protein (p.Tyr2202Asp). This variant is present in population databases (rs730881311, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or head and neck squamous carcinoma (PMID: 26689913, 29522266). ClinVar contains an entry for this variant (Variation ID: 181882). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein 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. -

not provided Uncertain:2
-
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.Tyr2202Asp variant was identified by Mansouri (2013) in an individual with chronic myelogenous leukemia. The variant was also identified in dbSNP (ID: rs730881311) as “With Uncertain significance allele”, and in ClinVar (as uncertain significance by GeneDx, Ambry Genetics, Invitae, University of Chicago, and Color Genomics). The variant was not identified in the Cosmic, MutDB, LOVD 3.0, or ATM-LOVD database. The variant was identified in control databases in 3 of 245856 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15300 chromosomes (freq: 0.00007), European (Non-Finnish) in 2 of 111502 chromosomes (freq: 0.000018); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Tyr2202 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. -

Apr 11, 2025
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 has a deleterious effect on protein structure/function; Observed in individuals with breast and other cancers (PMID: 24172824, 26689913, 29522266); This variant is associated with the following publications: (PMID: 24172824, 27720647, 29522266, 26689913, 33436325, 23532176) -

Hereditary cancer-predisposing syndrome Uncertain:2
Mar 27, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces tyrosine with aspartic acid at codon 2202 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on 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 (PMID: 28779002, 29522266) and head and neck squamous cell carcinoma (PMID: 26689913). In a large international case-control study, this variant was reported in 5/60461 breast cancer cases and 8/53453 controls (OR=0.553, 95%CI 0.181 to 1.689, p-value=0.406; PMID: 33471991). This variant has been identified in 3/251042 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. -

Jan 28, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Y2202D variant (also known as c.6604T>G), located in coding exon 45 of the ATM gene, results from a T to G substitution at nucleotide position 6604. The tyrosine at codon 2202 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration has been reported in 3/13087 breast cancer cases and 2/5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This variant was reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial cancer of breast Uncertain:1Benign:1
Mar 30, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 07, 2024
Myriad Genetics, Inc.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Breast and/or ovarian cancer Uncertain:1
Nov 04, 2020
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent 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
0.13
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.25
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.18
T;T
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.71
T;.
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.021
D;D
Sift4G
Benign
0.073
T;T
Polyphen
1.0
D;D
Vest4
0.83
MVP
0.96
MPC
0.70
ClinPred
0.97
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.75
gMVP
0.60

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: rs730881311; hg19: chr11-108196068; API