rs148993589

chr11-108289727-A-Cchr11-108289727-A-Gchr11-108289727-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000051.4(ATM):c.4362A>C(p.Lys1454Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,818 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1454R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:7
• Conservation: PhyloP100: 2.89

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09226492).
• BP6: Variant 11-108289727-A-C is Benign according to our data. Variant chr11-108289727-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127386.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Benign=2, Likely_benign=4}. Variant chr11-108289727-A-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4362A>C	p.Lys1454Asn	missense_variant	29/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4362A>C	p.Lys1454Asn	missense_variant	29/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000303 AC: 76 AN: 251182 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135770

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000599

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000413 AC: 603 AN: 1461462 Hom.: 1 Cov.: 31 AF XY: 0.000425 AC XY: 309 AN XY: 727034

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000504

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74510

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000439 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000327

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:8 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Lys1454Asn variant was identified in 6 of 10774 proband chromosomes (frequency: 0.00056) from individuals or families with breast and colon cancer (Barbazetto_2008, Broeks_2008, Maillet_2002, Pearlman_2016, Tavtigian_2009, Teraoka_2001). The variant was also identified in dbSNP (ID: rs148993589) as “With Uncertain significance allele”, ClinVar (as benign by Ambry Genetics and as uncertain significance by GeneDx, Invitae, and Color Genomics), Clinvitae (as in ClinVar), and in Cosmic. The variant was not identified in the COGR, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 84 of 276958 chromosomes at a frequency of 0.000303 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.000042), Other in 1 of 6452 chromosomes (freq: 0.000155), European (Non-Finnish) in 76 of 126554 chromosomes (freq: 0.000601), Ashkenazi Jewish in 3 of 10138 chromosomes (freq: 0.000296), and European (Finnish) in 3 of 25770 chromosomes (freq: 0.000116); it was not observed in the Latino, East Asian, and South Asian populations. The p.Lys1454Asn residue is not conserved in mammals and 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 was identified in a laboratory in one individual with a co-occurring pathogenic BRCA2 variant p.Gln2943ArgfsX33 in a family with HBOC, increasing the likelihood that the p.Lys1454Asn variant does not have clinical significance. 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	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 07, 2023	The frequency of this variant in the general population, 0.00058 (75/129022 chromosomes in European (Non-Finnish) subpop subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28779002 (2017), 19781682 (2009), 17393301 (2008), 11505391 (2001)), endometrial cancer (PMID: 27443514 (2016)), colorectal cancer (PMID: 27978560 (2016)), pancreatic cancer (PMID: 33436325 (2021)), melanoma (PMID: 34262154 (2021)), or chronic lymphocytic leukemia (PMID: 28652578 (2017)), as well as an individual with perifoveal telangiectasia (PMID: 18502988 (2008)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 07, 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 disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, endometrial, or colon cancer (Maillet 2002, Broeks 2008, Tavtigian 2009, Lu 2015, Tung 2015, Ring 2016, Decker 2017, Pearlman 2017, Hampel 2018, Hauke 2018); Observed in an individual with idiopathic perifoveal telangiectasia (Barbazetto 2008); This variant is associated with the following publications: (PMID: 19781682, 12362033, 17393301, 22529920, 26689913, 12697903, 11505391, 27978560, 27443514, 25925381, 28779002, 25186627, 29522266, 29596542, 30197789, 10425038, 27150160, 25759019, 18502988, 33471991) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 03, 2017	The p.Lys1454Asn variant has been reported in individuals with breast cancer (Broeks 2008 Teraoka 2001, Tavtigian 2009), endometrial cancer (Ring 2016), and idiopathic perifoveal telangiectasia (Barbazetto 2008) but has not been reported in association with ataxia telangiectasia. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.03 percent (identified on 84 out of 276,958 chromosomes) and has been reported to ClinVar (Variation ID: 127386). The lysine at position 1454 is moderately conserved (Alamut v.2.9.0) and computational analyses of the effects of the p.Lys1454Asn variant on protein structure and function predict a neutral effect (SIFT: tolerated, Align GVGC: C0 (benign), PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Lys1454Asn variant with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ATM: PM2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 2015	This alteration is classified as 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	Aug 12, 2020	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The amino acid Lys at position 1454 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The missense variant c.4362A>C (p.Lys1454Asn) in ATM gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Lys1454Asn variant is reported with the allele frequency of 0.02937% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Lys1454Asn in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2023	Variant summary: ATM c.4362A>C (p.Lys1454Asn) results in a non-conservative amino acid change in 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 0.0003 in 259596 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0003 vs 0.004), allowing no conclusion about variant significance. c.4362A>C has been reported in the literature in individuals undergoing multigene panel testing for a variety of hereditary cancers without strong evidence for causality (e.g. Broeks_2008, Tavtigian_2009, Tung_2015, Dalmasso_2021, Karlsson_2021). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. 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: 17393301, 18502988, 19781682, 22529920, 20305132, 17623063, 25186627, 10425038, 28652578, 30447919, 30584090, 31173964, 33436325, 34262154). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=5) and VUS (n=8). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of any concrete evidence supporting an actionable outcome in over 5 years of review performed at our laboratory and in the literature as evidence outlined above, the variant was re-classified as likely benign. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Division of Medical Genetics, University of Washington

Nov 25, 2019

This variant has been reported in the literature in individuals with breast cancer and in an individual with endometrial cancer (Teraoka 2001, Broeks 2008, Tavtigian 2009, Lu 2015, Ring 2016), as well as in an individual with idiopathic perifoveal telangiectasia (Barbazetto 2008). This variant has an overall allele frequency of 0.0003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;.;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N;N;.
REVEL	Benign	0.10
Sift	Benign	0.053	T;T;.
Sift4G	Uncertain	0.057	T;T;D
Polyphen		0.27	B;B;.
Vest4		0.57
MutPred		0.14		Loss of ubiquitination at K1454 (P = 0.0183);Loss of ubiquitination at K1454 (P = 0.0183);.;
MVP		0.81
MPC		0.16
ClinPred		0.095	T
GERP RS		3.3
Varity_R		0.34
gMVP		0.53

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

Other links and lift over

dbSNP: rs148993589; hg19: chr11-108160454; COSMIC: COSV53750192; COSMIC: COSV53750192;