rs146382972

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000051.4(ATM):​c.334G>A​(p.Ala112Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000146 in 1,604,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense, splice_region

Scores

1
6
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:9

Conservation

PhyloP100: 5.35
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 Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.016045034).
BP6
Variant 11-108235672-G-A is Benign according to our data. Variant chr11-108235672-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127370.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=4, Uncertain_significance=4}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000722 (110/152254) while in subpopulation AFR AF= 0.00248 (103/41552). AF 95% confidence interval is 0.00209. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.334G>A p.Ala112Thr missense_variant, splice_region_variant Exon 5 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.334G>A p.Ala112Thr missense_variant, splice_region_variant Exon 5 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.000730
AC:
111
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00249
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000208
AC:
52
AN:
250218
Hom.:
0
AF XY:
0.000133
AC XY:
18
AN XY:
135384
show subpopulations
Gnomad AFR exome
AF:
0.00280
Gnomad AMR exome
AF:
0.000203
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000861
AC:
125
AN:
1452478
Hom.:
0
Cov.:
30
AF XY:
0.0000678
AC XY:
49
AN XY:
723078
show subpopulations
Gnomad4 AFR exome
AF:
0.00280
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000466
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000181
Gnomad4 OTH exome
AF:
0.000216
GnomAD4 genome
AF:
0.000722
AC:
110
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.000699
AC XY:
52
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.00248
Gnomad4 AMR
AF:
0.000262
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:
0.000945
Alfa
AF:
0.000159
Hom.:
0
Bravo
AF:
0.000865
ESP6500AA
AF:
0.00227
AC:
10
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000214
AC:
26

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Jun 05, 2018
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 12, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25318351, 25980754, 17333338, 27443514, 27720647, 19781682, 28779002, 23555315, 33095795) -

Sep 22, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Feb 14, 2017
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 11, 2019
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 10, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:1
Oct 07, 2016
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 16, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ATM c.334G>A (p.Ala112Thr) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 250408 control chromosomes (gnomAD, Hirsch_2008), predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant has also been found in 13/2559 (carrier freq=0.00508) African American women over the age of 70 without history of cancer (FLOSSIES dataset). c.334G>A has been reported in the literature in individuals affected with Breast Cancer, Lynch Syndrome, endometrial carcinoma, cerebellar ataxia, primary ovarian insufficiency and PDAC (examples: Tung_2014, Yurgelun_2015, Ring_2016, Coutelier_2018, Mullins_2019, Weitzel_2019, Franca_2020, Zimmermann_2021), but it was also reported in healthy controls (examples: Hirsch_2008, Weitzel_2019). 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. Ten ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, three as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

Ataxia-telangiectasia syndrome Benign:2
Aug 22, 2023
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
May 23, 2017
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

ATM-related disorder Uncertain:1
May 03, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The ATM c.334G>A variant is predicted to result in the amino acid substitution p.Ala112Thr. This variant has been reported in two individuals with breast cancer (Tung et al. 2014. PubMed ID: 25186627; Mullins and Gupta. 2019. PubMed ID: 31719806), in an individual with endometrial cancer (Ring et al. 2016. PubMed ID: 27443514, Table S2), an individual with primary ovarian insufficiency (França et al. 2020. PubMed ID: 33095795), and in at least two individuals undergoing Lynch syndrome genetic testing (Yorczyk et al. 2014. PubMed ID: 25318351, Table 2; Yurgelun et al. 2015. PubMed ID: 25980754, Table S2). It has also been reported in controls from breast cancer cohort studies (Hirsch et al. 2007. PubMed ID: 17333338; Tavtigian et al. 2009. PubMed ID: 19781682. Table S2). This variant is reported in 0.27% of alleles in individuals of African descent in gnomAD, which is significantly more common than other known disease-causing ATM variants. In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127370/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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.Ala112Thr variant was identified in 4 of 17948 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer or Lynch syndrome and was present in 2 of 4988 control chromosomes (frequency: 0.0004) from healthy individuals (Haiman 2013, Hirsch 2008, Ring 2016, Tavtigian 2009, Yorczyk 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs146382972) as "With other allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by GeneDx and five other submitters), and MutDB. The variant was not identified in COGR, Cosmic, or LOVD 3.0 databases. The variant was identified in control databases in 74 of 276196 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 66 of 23976 chromosomes (freq: 0.003), Other in 1 of 6434 chromosomes (freq: 0.0002), and Latino in 7 of 34316 chromosomes (freq: 0.0002), while the variant was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala112 residue is 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) 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. -

Familial cancer of breast Benign:1
Apr 18, 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]. -

Hereditary breast ovarian cancer syndrome Benign:1
Apr 19, 2022
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.32
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.063
.;T;.;T;T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D;D;.;D
M_CAP
Benign
0.069
D
MetaRNN
Benign
0.016
T;T;T;T;T
MetaSVM
Benign
-0.35
T
MutationAssessor
Benign
1.9
.;L;.;L;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.9
N;N;.;N;.
REVEL
Benign
0.11
Sift
Uncertain
0.011
D;D;.;D;.
Sift4G
Uncertain
0.019
D;D;D;D;D
Polyphen
0.87
.;P;.;P;.
Vest4
0.13, 0.060, 0.18
MVP
0.91
MPC
0.27
ClinPred
0.033
T
GERP RS
4.7
Varity_R
0.21
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs146382972; hg19: chr11-108106399; API