11-108249096-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000051.4(ATM):​c.1229T>C​(p.Val410Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00282 in 1,613,936 control chromosomes in the GnomAD database, including 11 homozygotes. 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 0.0018 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0029 ( 9 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

1
9
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:26O:1

Conservation

PhyloP100: 7.12
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 Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.012444019).
BP6
Variant 11-108249096-T-C is Benign according to our data. Variant chr11-108249096-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127332.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=8, Likely_benign=13, not_provided=1}. Variant chr11-108249096-T-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00185 (281/152280) while in subpopulation AMR AF= 0.00392 (60/15290). AF 95% confidence interval is 0.00313. There are 2 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.1229T>C p.Val410Ala missense_variant Exon 9 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.1229T>C p.Val410Ala missense_variant Exon 9 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.00185
AC:
281
AN:
152162
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000603
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00393
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00275
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00222
AC:
558
AN:
251102
Hom.:
2
AF XY:
0.00229
AC XY:
311
AN XY:
135716
show subpopulations
Gnomad AFR exome
AF:
0.000924
Gnomad AMR exome
AF:
0.00298
Gnomad ASJ exome
AF:
0.00417
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000925
Gnomad NFE exome
AF:
0.00339
Gnomad OTH exome
AF:
0.00180
GnomAD4 exome
AF:
0.00292
AC:
4273
AN:
1461656
Hom.:
9
Cov.:
33
AF XY:
0.00278
AC XY:
2021
AN XY:
727132
show subpopulations
Gnomad4 AFR exome
AF:
0.000836
Gnomad4 AMR exome
AF:
0.00304
Gnomad4 ASJ exome
AF:
0.00291
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000225
Gnomad4 NFE exome
AF:
0.00346
Gnomad4 OTH exome
AF:
0.00290
GnomAD4 genome
AF:
0.00185
AC:
281
AN:
152280
Hom.:
2
Cov.:
32
AF XY:
0.00192
AC XY:
143
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.000601
Gnomad4 AMR
AF:
0.00392
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.00275
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00328
Hom.:
2
Bravo
AF:
0.00230
TwinsUK
AF:
0.00297
AC:
11
ALSPAC
AF:
0.00363
AC:
14
ESP6500AA
AF:
0.000909
AC:
4
ESP6500EA
AF:
0.00221
AC:
19
ExAC
AF:
0.00216
AC:
262
EpiCase
AF:
0.00278
EpiControl
AF:
0.00373

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:26Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:6
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 21, 2019
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 11, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ATM: BS2 -

Aug 13, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 10, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The ATM c.1229T>C (p.Val410Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 270/126714 control chromosomes (2 homozygotes) at a frequency of 0.0021308, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0005001), suggesting this variant is likely a benign polymorphism. This variant has been found in patients with various types of cancer, including breast cancer, uterine serous carcinoma, lymphoma, chronic lymphocytic leukemia, and melanoma. It has not been reported in patients with ataxia-telangiectasia. Two large case-control studies showed that this variant is not associated with breast cancer (Tavtigian 2009; Haiman 2013). Thus available patient and control data show that this variant is a polymorphism found in patients as well as unaffected individuals. In addition, three clinical laboratories have classified this variant as benign/likely benign albeit another lab consider it as uncertain significance, all without evidence to independently evaluate. Taken together, this variant has been classified as Likely benign until more evidence becomes available. -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:5
Jul 13, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

May 23, 2018
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 15, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Nov 14, 2017
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 05, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 22, 2016
Vantari Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Benign:6
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 18, 2017
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 19, 2020
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 15, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:5Other:1
Nov 29, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 08, 2020
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 01, 2015
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

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

- -

Nov 23, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
Jun 12, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Carcinoma of colon Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The ATM p.Val410Ala variant was identified in 5 of 1492 proband chromosomes (frequency: 0.003) from Dutch and Austrian individuals or families with breast cancer or ovarian cancer, and individuals with pediatric ALL (acute lymphocytic leukemia), and was identified in 2 of 644 chromosomes (frequency: 0.003) from healthy individuals (Broeks_2008_17393301, Thorstenson_2003_12810666, Liberzon_2004_14695997). The variant was also identified as a somatic mutation in 2 studies screening CRCs and lymphomas (Dallol_2016_ 27146902, Fang_2003_12149228). The variant was identified in dbSNP (ID: rs56128736) “With other allele”, ClinVar (wth conflicting interpretations of pathogenicity; submitters: benign by Ambry Genetics, GeneDx, and Invitae, likely benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), uncertain significance by Vantari Genetics and Genetic Services Laboratory (University of Chicago), and classification not provided by ITMI), Clinvitae (4x), Cosmic (7x in malignant melanoma, lymphoid neoplasm and carcinoma of the lung), LOVD 3.0, and in control databases in 582 (3 homozygous) of 276862 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 18 of 24018 chromosomes (freq: 0.0007), Other in 14 of 6458 chromosomes (freq: 0.002), Latino in 105 of 34390 chromosomes (freq: 0.003), European Non-Finnish in 401 (2 homozygous) of 126452 chromosomes (freq: 0.003), Ashkenazi Jewish in 41 (1 homozygous) of 10138 chromosomes (freq: 0.004), European Finnish in 3 of 25762 chromosomes (freq: 0.0001), while not observed in the East Asian and South Asian populations. The variant was not identified in GeneInsight-COGR or MutDB. The p.Val410 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Ala 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

ATM-related disorder Benign:1
Feb 12, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cancer of breast Benign:1
Apr 25, 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]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.088
.;T;T
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.77
T;T;.
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.012
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.6
.;M;M
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-2.6
D;N;N
REVEL
Benign
0.26
Sift
Uncertain
0.0040
D;D;D
Sift4G
Uncertain
0.0070
D;D;D
Polyphen
0.43
.;B;B
Vest4
0.42, 0.47
MVP
0.99
MPC
0.23
ClinPred
0.065
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.13
gMVP
0.48

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: rs56128736; hg19: chr11-108119823; COSMIC: COSV53726818; COSMIC: COSV53726818; API