rs754275014

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000051.4(ATM):c.712A>G(p.Ile238Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I238T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 1.75

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]

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13877034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.712A>G	p.Ile238Val	missense_variant	7/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.712A>G	p.Ile238Val	missense_variant	7/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251040

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461614

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727110

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:

0.0000225

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 19, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2023	This missense variant replaces isoleucine with valine at codon 238 of the ATM protein. Computational prediction suggests that this variant may not impact 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, ovarian cancer, or colorectal cancer (PMID: 26689913, 27978560, 30287823, 33471991). This variant has been identified in 4/251040 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. -

Ataxia-telangiectasia syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 238 of the ATM protein (p.Ile238Val). This variant is present in population databases (rs754275014, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer, and ovarian cancer (PMID: 26689913, 27978560, 30287823). ClinVar contains an entry for this variant (Variation ID: 186210). 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 provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 01, 2020	The ATM c.712A>G; p.Ile238Val variant (rs754275014) is reported in the literature in an individual with colorectal cancer (Pearlman 2017), and individuals with breast cancer but was also reported in healthy controls (Momozawa 2018). This variant is reported in the ClinVar database (Variation ID: 186210). It is found in the general population with an overall allele frequency of 0.002% (4/251040 alleles) in the Genome Aggregation Database. The isoleucine at codon 238 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. Pearlman R et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017 Apr 1;3(4):464-471. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2023	Observed in individuals with breast, ovarian, and colon cancer, and also in controls (Lu et al., 2015; Pearlman et al., 2017; Momozawa et al., 2018; Dorling et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 30287823, 27978560, 33471991) -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 23, 2020	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.61

Cadd

Benign

Dann

Benign

0.83

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.67

T;T;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

0.96

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.041

Sift

Benign

0.49

T;T;T

Sift4G

Benign

0.69

T;T;T

Polyphen

0.0020

.;B;B

Vest4

0.12, 0.11

MutPred

0.26

Loss of catalytic residue at L243 (P = 0.0977);Loss of catalytic residue at L243 (P = 0.0977);Loss of catalytic residue at L243 (P = 0.0977);

MVP

0.80

MPC

0.10

ClinPred

0.035

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.098

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over