11-108227797-C-T

Position:

chr11-108227797-C-T

Variant summary

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

The NM_000051.4(ATM):c.94C>T(p.Arg32Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,490 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 1.32

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09439537).

BP6

Variant 11-108227797-C-T is Benign according to our data. Variant chr11-108227797-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142913.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.94C>T	p.Arg32Cys	missense_variant	3/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.94C>T	p.Arg32Cys	missense_variant	3/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152080

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000876

AC:

AN:

251158

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461410

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000673

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

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:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2024	Variant summary: ATM c.94C>T (p.Arg32Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage (IPR021668) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251158 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.8e-05 vs 0.004), allowing no conclusion about variant significance. c.94C>T has been reported in the literature in at-least one individual affected with Colorectal cancer, without strong evidence for causality (deOliveira-Garcia_2022). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 6/53461 controls and 2/60466 case (Dorling_2021 through LOVD). In another case-control studies of Biliary tract cancer, this variant was not found in 1,229 cases but was reported at 0.001% in 37,583 controls (Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or other ATM-related diseases. 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: 33471991, 36243179, 35534704). ClinVar contains an entry for this variant (Variation ID: 142913, Likely benign, n=3; VUS, n=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Ataxia-telangiectasia syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 27, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 20, 2016	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate activity similar to wild type in DNA damage and cell cycle checkpoint assays (Lesport et al., 2018); Observed in individuals with a personal history of breast or other cancers (Petereit et al., 2013; Momozawa et al., 2018; Mittal et al., 2022); This variant is associated with the following publications: (PMID: 24416720, 29423082, 36200007, 30287823) -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ATM p.Arg32Cys variant was identified in 1 of 400 proband chromosomes (frequency: 0.003) from American Indian and non-American Indian cancer individuals undergoing radiation therapy (Petereit 2013). The variant was also identified in dbSNP (ID: rs148061139) â€šÃ„ÃºWith Uncertain significanceâ€šÃ„Ã¹ allele, ClinVar (classified as uncertain significance by Ambry Genetics, Invitae and GeneDx), Clinvitae (3X as uncertain significance) and Cosmic (1X in an adenocarcinoma of the large intestine). The variant was not identified in GeneInsight-COGR, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 24 of 277068 chromosomes at a frequency of 0.00009 in the following populations: South Asian in 17 of 16510 chromosomes (freq. 0.00055), East Asian in 2 of 8654 chromosomes (freq. 0.0002), and European (Non-Finnish) in 2 of 66696 chromosomes (freq. 0.00003) increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). Although the p.Arg32 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cys variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 08, 2019

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: PP3,BP1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D;D;D;D;.;.;.;.;.;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.094

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-4.4

D;N;D;D;.;N;.;.;.;.;.

REVEL

Benign

0.18

Sift

Uncertain

0.0010

D;D;D;D;.;D;.;.;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;.;.;.;D;D

Polyphen

1.0, 0.026

.;D;.;.;.;D;B;B;B;B;.

Vest4

0.42, 0.40, 0.42, 0.36

MVP

0.85

MPC

0.27

ClinPred

0.27

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.32

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