11-108250909-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000051.4(ATM):​c.1444A>C​(p.Lys482Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000065 in 1,614,208 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

7
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17B:4

Conservation

PhyloP100: 4.38
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 -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.102552325).
BP6
Variant 11-108250909-A-C is Benign according to our data. Variant chr11-108250909-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127338.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=14, Likely_benign=4}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.1444A>C p.Lys482Gln missense_variant Exon 10 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.1444A>C p.Lys482Gln missense_variant Exon 10 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000955
AC:
24
AN:
251370
Hom.:
0
AF XY:
0.0000883
AC XY:
12
AN XY:
135850
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.000194
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000691
AC:
101
AN:
1461870
Hom.:
0
Cov.:
36
AF XY:
0.0000701
AC XY:
51
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
0.0000863
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152338
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.0000240
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000767
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000218
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:17Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3Benign:2
Sep 02, 2020
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. -

Nov 05, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Oct 14, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 15, 2024
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The missense variant NM_000051.4(ATM):c.1444A>C (p.Lys482Gln) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is observed in one or more well-documented healthy adults. There is a small physicochemical difference between lysine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene ATM has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 2.52. The gene ATM contains 170 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.Lys482Gln missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1444 in ATM is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

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

- -

not provided Uncertain:4
Jun 12, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast and colon cancers, as well both cases and controls in a breast cancer study (PMID: 28779002, 28135145, 25186627, 29522266, 34326862, 34399810, 34371384, 33471991, 36035419); This variant is associated with the following publications: (PMID: 28779002, 25231023, 25528188, 28528518, 28135145, 25186627, 28873162, 29522266, 28652578, 31159747, 31658756, 34399810, 34371384, 34803902, 36035419, 33471991, 34326862, 36980780) -

-
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.Lys482Gln variant was identified in 1 of 170 proband chromosomes (frequency: 0.006) from individuals or families with hereditary breast and ovarian cancer (Cock-Rada_2017). The p.Lys482Gln variant was also found in one study to be a recurrent variant in Mullerian adenosarcoma occurring in 3 of 36 chromosomes (frequency: 0.083) Howitt_2015). The variant was also identified in the following databases: dbSNP (ID: rs202173660) as “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, Ambry Genetics, Invitae, and Color Genomics), Clinvitae (3x), and Cosmic (1x in endometrial cancer). The variant was not identified in MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in control databases in 25 of 246152 chromosomes at a frequency of 0.000102 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 15302 chromosomes (freq: 0.000065), Other in 1 of 5482 chromosomes (freq: 0.000182), Latino in 1 of 33566 chromosomes (freq: 0.00003), European (Non-Finnish) in 22 of 111630 chromosomes (freq: 0.000197); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Lys482 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. 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. -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 05, 2018
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:3Benign:1
Jul 02, 2018
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 2018
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 18, 2020
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:3Benign:1
Oct 10, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 03, 2023
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]. -

Jun 20, 2024
Department of Human Genetics, Hannover Medical School
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 31, 2023
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ATM c.1444A>C (p.Lys482Gln) missense has a maximum subpopulation frequency of 0.017% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant was identified in an individual with breast and/or ovarian cancer undergoing multi-gene panel testing (PMID: 28528518). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not specified Uncertain:3
Aug 31, 2022
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

DNA sequence analysis of the ATM gene demonstrated two sequence changes in this gene. The first sequence change, c.1444A>C, in exon 10 results in an amino acid change, p.Lys482Gln. This sequence has been reported in individuals with breast, ovarian, and/or colorectal cancer (PMID: 28135145, 28528518, 33471991, 28779002, 34371384, 34399810) and has also been reported in healthy controls (PMID: 33471991, 28779002). This sequence change has been described in the gnomAD database with a frequency of 0.017% in the European subpopulation (dbSNP rs202173660). The p.Lys482Gln change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys482Gln substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Lys482Gln change remains unknown at this time. -

Aug 16, 2024
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.1444A>C (p.Lys482Gln) 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 9.5e-05 in 251370 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (9.5e-05 vs 0.001), additionally, this variant was also found in 1/7325 European Americans over the age of 70 without a history of cancer (FLOSSIES dataset). c.1444A>C has been reported in the literature in individuals affected with various types of cancer (HBOC, colorectal cancer, Mullerian adenosarcoma) without strong evidence for causality (Cock-Rada_2017, Yurgelun_2017, Howitt_2019, Tsaousis_2019, Urbina-Jara_2019, Mandelker_2017, Nunziato_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MUTYH c.849+3A>C, Nunziato_2022), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28528518, 25231023, 28873162, 36035419, 31159747, 31658756, 28135145). ClinVar contains an entry for this variant (Variation ID: 127338). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

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

- -

ATM-related disorder Uncertain:1
Apr 27, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The ATM c.1444A>C variant is predicted to result in the amino acid substitution p.Lys482Gln. This variant has been reported in individuals with colorectal, breast, or ovarian cancer (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; File S2, Howitt et al. 2014. PubMed ID: 25231023; Cock-Rada et al. 2018. PubMed ID: 28528518), but has also been reported in three healthy control individuals in a study of patients with chronic lymphocytic leukemia (Table S6, Tiao et al. 2017. PubMed ID: 28652578). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127338/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.32
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.086
.;T;T
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.82
T;T;.
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Uncertain
2.6
.;M;M
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Benign
0.16
Sift
Benign
0.059
T;T;T
Sift4G
Uncertain
0.028
D;T;T
Polyphen
0.65
.;P;P
Vest4
0.33, 0.38
MVP
0.82
MPC
0.26
ClinPred
0.074
T
GERP RS
5.8
Varity_R
0.50
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs202173660; hg19: chr11-108121636; COSMIC: COSV53727606; COSMIC: COSV53727606; API