rs529296539

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5BS2

The NM_000051.4(ATM):c.8495G>A(p.Arg2832His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,613,710 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R2832C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 2 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:1O:1

Conservation

PhyloP100: 9.98

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:

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-108345818-C-T is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.8495G>A	p.Arg2832His	missense_variant	58/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.8495G>A	p.Arg2832His	missense_variant	58/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251276

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000855

AC:

125

AN:

1461538

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000707

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Arg2832His variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs529296539) as "With Likely pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and two other submitters). The variant was identified in control databases in 31 of 276996 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.00004), Latino in 1 of 34388 chromosomes (freq: 0.00003), European in 9 of 126562 chromosomes (freq: 0.00007), East Asian in 4 of 18866 chromosomes (freq: 0.0002), and South Asian in 16 of 30774 chromosomes (freq: 0.0005), while the variant was not observed in the Other, Ashkenazi Jewish, or Finnish populations. The p.Arg2832 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2832 of the ATM protein (p.Arg2832His). This variant is present in population databases (rs529296539, gnomAD 0.05%). This missense change has been observed in individual(s) with lung, breast or ovarian and pancreatic cancer (PMID: 26689913, 28726808, 28779002, 30303537, 33552952). ClinVar contains an entry for this variant (Variation ID: 133638). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. This variant disrupts the p.Arg2832 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9443866, 10817650, 10873394, 12552559, 18634022). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, pancreatic, or other cancers (Lu et al., 2015; Decker et al., 2017; Chaffee et al., 2018; Girard et al., 2019; Kadri et al., 2020; Castillo-Guardiola et al., 2022; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 27198204, 18634022, 24728327, 24841718, 26689913, 28779002, 29338072, 28726808, 29641532, 28652578, 33552952, 31422574, 32736562, 36480066, 14706517, 20305132, 35273907, 33471991, 34720947, 34174931, 21665257, 30093976, 35130390, 35085662, 23532176, 30303537, 35245693, 35264596) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 17, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 17, 2023	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35264596 (2022), 33552952 (2020), 30303537 (2019), 28779002 (2017), 26689913 (2015), 20305132 (2010)), pancreatic cancer (PMID: 28726808 (2018)), and lung cancer (PMID: 26689913 (2015)). This variant has also been reported in unaffected individuals (PMID: 31422574 (2019), 29641532 (2018), 28652578 (2017), 24728327 (2014)). The frequency of this variant in the general population, 0.00049 (15/30602 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 29, 2022	The p.R2832H variant (also known as c.8495G>A), located in coding exon 57 of the ATM gene, results from a G to A substitution at nucleotide position 8495. The arginine at codon 2832 is replaced by histidine, an amino acid with highly similar properties. A different missense alteration affecting the same amino acid, p.R2832C, has been reported as pathogenic by multiple groups (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Becker-Catania S et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). The p.R2832H alteration was identified in 1/1358 non-cancer control individuals and was not observed in 57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This alteration was identified in 1/1207 cases of BRCA negative French women was not observed in 1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This alteration has also been identified 1/302 individuals with pancreatic cancer (Chaffee KG et al. Genet Med, 2018 01;20:119-127). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2023	This missense variant replaces arginine with histidine at codon 2832 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 and/or ovarian cancer (PMID: 20305132, 30303537, 33552952, 35264596), pancreatic cancer (PMID: 28726808) and gastric cancer (PMID: 14706517), as well as in unaffected individuals (PMID: 24728327, 31422574). In a large breast cancer case-control study, this variant was observed in 9/60457 cases and 3/53458 controls, showing inconclusive association with disease (OR=2.653, 95%CI 0.718 to 9.799, p-value=0.155; PMID: 33471991). This variant has been identified in 31/282644 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same position, p.Arg2832Cys and p.Arg2832Pro, are considered to be disease-causing (ClinVar variation ID: 127459, 429065), suggesting that the arginine amino acid at this position is important for the protein function. 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 submitter	curation	Sema4, Sema4	Sep 13, 2021	- -

not specified

Uncertain:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2023	Variant summary: ATM c.8495G>A (p.Arg2832His) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) and ATM, catalytic domain (IPR044107) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251276 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00012 vs 0.001), allowing no conclusion about variant significance. c.8495G>A has been reported in the literature in individuals affected with various forms of cancer including gastric, pancreatic, breast, and lung cancer (e.g., Zhang_2004, Chaffee_2018, Girard_2019, Guindalini_2022, Bernstein_2010, Castillo-Guardiola_2022, Lu_2015). However the variant has also been detected in healthy control individuals (e.g., Bodian_2014, Tiao_2017). These data therefore do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same codon (c.8494C>T/p.Arg2832Cys) has been reported as pathogenic in ClinVar (CV ID 127459) and is associated with several types of cancer (HGMD). The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 24728327, 35245693, 28726808, 30303537, 35264596, 26689913, 28652578, 30374176, 14706517). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=12) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 26, 2018	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 26, 2021

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Jan 10, 2023

The ATM c.8495G>A (p.Arg2832His) missense change has a maximum subpopulation frequency of 0.049% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 20305132), gastric cancer (PMID: 14706517), and pancreatic cancer (PMID: 28726808), and it has also been observed in control subjects (PMID: 24728327, 30303537, 31422574). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). Missense variants affecting the same amino acid residue, p.Arg687Cys, and p.Arg687Pro, have been reported as pathogenic in individuals with ataxia telangiectasia (PMID: 9443866, 10817650, 10873394, 18634022). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;.

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Benign

-0.74

MutationAssessor

Benign

-0.095

N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

1.0

N;N

REVEL

Uncertain

0.47

Sift

Benign

0.22

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.77

P;P

Vest4

0.88

MutPred

0.79

Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);

MVP

0.91

MPC

0.22

ClinPred

0.10

GERP RS

5.5

Varity_R

0.56

gMVP

0.69

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