11-108251932-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000051.4(ATM):c.1703G>T(p.Arg568Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. R568G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:9
• Conservation: PhyloP100: 0.780

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012072533).
• BP6: Variant 11-108251932-G-T is Benign according to our data. Variant chr11-108251932-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140916.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=6, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.1703G>T	p.Arg568Ile	missense_variant	11/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.1703G>T	p.Arg568Ile	missense_variant	11/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00317

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: 0.000478

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 251228 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000124 AC: 181 AN: 1461552 Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 727074

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:4 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 03, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 20, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 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	Aug 20, 2020	- -

not specified Uncertain:1 Benign:2

Uncertain significance, 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	Athena Diagnostics	Sep 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 18, 2021	Variant summary: ATM c.1703G>T (p.Arg568Ile) results in a non-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 allele was found at a frequency of 0.00019 in 276984 control chromosomes, predominantly at a frequency of 0.0034 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1703G>T has been reported in the literature in individuals affected with Colorectal cancer or prostate cancer (Yurgelun_2016, Paulo_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic/likely pathogenic variants have been reported (ATM c.8934_8935del, p.E2979Afs*9; CHEK2 c.1283C>T, p.Ser428Phe, Yurgelun_2016 and internal data), providing supporting evidence for a benign role. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign n=1, Likely benign n=4, VUS n=7). Based on the evidence outlined above, the variant was classified as benign. -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 21, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	Observed in individuals with a personal and/or family history of melanoma, breast, ovarian, endometrial, colorectal or prostate cancer (Tung 2015, Decker 2017, Yurgelun 2017, Cock-Rada 2018, Paulo 2018, Pritchard 2018, Yehia 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26878173, 27997549, 28528518, 28135145, 28873162, 29641532, 28779002, 29684080, 28137924, 25186627, 29659569, 31658756) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2016	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ATM NM_000051.3 exon11 p.Arg568Ile (c.1703G>T): This variant has been reported in the literature in 1 individual with rectal cancer (Yurgelun 2017 PMID:28135145). This variant is present in 0.3% (36/10366) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-108122659-G-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:140916). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Of note, an additional variant at this same amino acid position (p.Arg568Lys) was identified in a patient with a history of cervix and breast cancer. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

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.Arg568Ile variant was identified in 1 of 170 proband chromosomes (frequency: 0.006) from individuals or families with breast and ovarian cancer (Cock-Rada 2017). The variant was also identified in the following databases: dbSNP (ID: rs200381392) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GenDx, Invitae) and Clinvitae. The variant was not identified in the COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 54 of 276984 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The p.Arg568 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	18
Dann	Benign	0.96
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.85	T;T;.
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.12	.;B;B
Vest4		0.36, 0.46
MVP		0.67
MPC		0.24
ClinPred		0.037	T
GERP RS		2.8
Varity_R		0.097
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200381392; hg19: chr11-108122659; COSMIC: COSV99588781; COSMIC: COSV99588781;