GeneBe

rs3205809

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000051.4(ATM):​c.2260C>A​(p.Gln754Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,613,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 5.19
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 -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.28367558).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATMNM_000051.4 linkc.2260C>A p.Gln754Lys missense_variant 15/63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.2260C>A p.Gln754Lys missense_variant 15/63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152180
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1460746
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
726732
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:
0.0000216
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74468
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000784
Hom.:
0
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 13, 2022PM2 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 22, 2024Observed in individuals with breast cancer (PMID: 20305132, 27978560); Observed in an individual with colorectal cancer who had a pathogenic variant in PMS2 (PMID: 27978560); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22529920, 20305132, 28779002, 28652578, 28873162, 33471991, 35467778, 34326862, 27978560) -
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenJun 13, 2023PM2_SUP -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The ATM p.Gln754Lysvariant was identified in 1 of 900 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Pearlman 2017). The variant was identified in dbSNP (ID: rs3205809) as “With Uncertain significance allele”, and in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx and two other submitters). The variant was identified in control databases in 1 of 30978 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017) in the European population in 1 of 15014 chromosomes (freq. 0.00006), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, South Asian or Finnish populations. The p.Gln754 residue is conserved in mammals however four out of five 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. -
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 03, 2023This missense variant replaces glutamine with lysine at codon 754 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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, 33471991) or prostate cancer (PMID: 35467778). This variant has been identified in 1/31402 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. -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 23, 2024The p.Q754K variant (also known as c.2260C>A), located in coding exon 14 of the ATM gene, results from a C to A substitution at nucleotide position 2260. The glutamine at codon 754 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer; however, this individual was also found to have a pathogenic mutation in the PMS2 gene (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). Computational analyses involving multiple in silico prediction models predict this alteration has uncertain potential for functional significance (George Priya Doss C et al. PLoS ONE, 2012 Apr;7:e34573). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jun 24, 2021- -
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Mar 07, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2022This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 754 of the ATM protein (p.Gln754Lys). This variant is present in population databases (rs3205809, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 141496). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 29, 2024Variant summary: ATM c.2260C>A (p.Gln754Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250960 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.2260C>A has been reported in the literature in individuals affected with Breast, Colorectal, or Prostate Cancer (examples: Bernstein_2010, Pearlman_2017, Brady_2022). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with a pathogenic variant has been reported (PMS2 c.1831dup, p.Ile611AsnfsX2), providing supporting evidence for a benign role (Pearlman_2017). 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: 20305132, 35467778, 27978560). ClinVar contains an entry for this variant (Variation ID: 141496). Based on the evidence outlined above, the variant was classified as uncertain significance. -
ATM-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 26, 2024The ATM c.2260C>A variant is predicted to result in the amino acid substitution p.Gln754Lys. This variant has been reported in a patient with colorectal cancer that also had a pathogenic variant in PMS2 (eTable 2 in Pearlman et al. 2017. PubMed ID: 27978560), and an individual in a study of ATM variants’ role in radiation-induced contralateral breast cancer in women (Supplementary Table 2 in Bernstein et al. 2010. PubMed ID: 20305132). This variant was identified in another individual with breast cancer in the UK (Decker B et al. 2017. PubMed ID: 28779002) and in an individual with prostate cancer (Brady L et al. 2022. PubMed ID: 35467778). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141496/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsOct 16, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.053
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
23
DANN
Benign
0.96
DEOGEN2
Benign
0.053
.;T;T
Eigen
Benign
0.093
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.82
T;T;.
M_CAP
Benign
0.052
D
MetaRNN
Benign
0.28
T;T;T
MetaSVM
Benign
-0.61
T
MutationAssessor
Uncertain
2.7
.;M;M
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.34
N;N;N
REVEL
Benign
0.28
Sift
Benign
0.57
T;T;T
Sift4G
Benign
0.12
T;T;T
Polyphen
0.17
.;B;B
Vest4
0.48, 0.34
MVP
0.83
MPC
0.24
ClinPred
0.94
D
GERP RS
6.2
Varity_R
0.55
gMVP
0.25

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: rs3205809; hg19: chr11-108128217; API