rs1800059

chr11-108299779-A-Cchr11-108299779-A-Gchr11-108299779-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):c.5071A>C(p.Ser1691Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,614,054 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1691T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:28 O:1
• Conservation: PhyloP100: 1.22

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008389473).
• BP6: Variant 11-108299779-A-C is Benign according to our data. Variant chr11-108299779-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127399.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Benign=10, Uncertain_significance=1, not_provided=1}. Variant chr11-108299779-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0016 (244/152324) while in subpopulation NFE AF= 0.00238 (162/68032). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5071A>C	p.Ser1691Arg	missense_variant	34/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5071A>C	p.Ser1691Arg	missense_variant	34/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00176 AC: 442 AN: 251232 Hom.: 2 AF XY: 0.00163 AC XY: 221 AN XY: 135760

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00292

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00205 AC: 2996 AN: 1461730 Hom.: 5 Cov.: 31 AF XY: 0.00193 AC XY: 1407 AN XY: 727172

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00275

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74482

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00238 Hom.: 1

Bravo AF: 0.00156

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00202 AC: 245

EpiCase AF: 0.00218

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:28 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1 Benign:9

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jun 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 26, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Ataxia-telangiectasia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:19431188). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Apr 21, 2016	- -

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2021	This variant is associated with the following publications: (PMID: 24728327, 11606401, 26979391, 28652578, 22420423, 22250480, 25742471, 14754616, 19431188, 9463314, 25980754, 26787654, 11505391, 27153395, 28202063, 28196074, 26933808, 28695297, 25133958, 28767289) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ATM: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2017	Variant summary: The ATM c.5071A>C (p.Ser1691Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 493/276958 control chromosomes (3 homozygotes) at a frequency of 0.001780, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this variant is likely a benign polymorphism. The variant has been reported in multiple breast cancer cases and cancer families, and in one ataxia-telangiectasia patient. None of the publications provide strong evidence for causality, lacking co-occurrence and co-segregation data, and often not providing the BRCA status of affected individuals. Multiple reputable clinical labs have classified this variant as likely benign/benign, without evidence to independently evaluate. Taken together, based on the prevalence in general population and by applying ACMG rules, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 20, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 04, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 14, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 23, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.5071A>T (p.Ser1691Arg) missense variant has an allele frequency of 0.18%, (476/268,092 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.30%, (354/117,946 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This variant has also been observed in homozygosis in 3 individuals of the gnomAD v2.1.1 non-neuro dataset (BS2_Supporting). Functional studies with the variant protein modelled in an ATM-null lymphoblastoid cell line and proper controls showed that: 1) the level of ATM protein was comparable to that of the positive control; 2) the ability of the modeled protein to phosphorylate Smc1, Nbs1, Chk2, and p53 following exposure of the cells to ionizing radiation and to autophosphorylate serine 1981 was also no different from the positive control; 3)The variant protein formed foci that colocalized with yH2AX following exposure to ionizing radiation (BS3; PMID:19431188). Therefore, this variant meets criteria to be classified as benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BS2_Supporting + BS3 (PMID: 33280026). -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 20, 2022

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Ser1691Arg variant was identified in 20 of 5886 proband chromosomes (frequency: 0.003) from American, Dutch and Lebanese individuals or families with breast cancer (high risk or familial or nonfamilial) or a history of Lynch syndrome associated cancer and/or polyps or individuals with unspecified cancer undergoing radiotherapy, and was identified in 4 of 3578 control chromosomes from healthy individuals (frequency: 0.001) (Petereit_2013_24416720, Broeks_2008_17393301, Jalkh_2017_28202063, Teraoka_2001_11505391, Bodian_2014_24728327, Yurgelun_2015_25980754 , Stredrick_2006_16652348). Functional studies using an expression construct to model ATM missense variants showed the variant’s level of ATM protein expression and kinase activity was comparable to wildtype (Barone_2009_19431188). The variant was identified in dbSNP (ID: rs1800059) “With other allele”, ClinVar (classified benign by Invitae, Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), likely benign by GeneDx, ARUP and classification not provided by ITMI), Clinvitae (3x), Cosmic (seen 2x in a malignant melanoma, 1x in a haematopoietic neoplasm and 3x in a carcinoma of the large intestine), LOVD 3.0 (1x), and was not identified MutDB. The variant was also identified in control databases in 493 (3 homozygous) of 276958 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 13 of 24030 chromosomes (freq: 0.0005), “Other” in 12 of 6458 chromosomes (freq: 0.002), Latino in 24 of 34416 chromosomes (freq: 0.0007), European Non-Finnish in 372 (2 homozygous) of 126472 chromosomes (freq: 0.003), and European Finnish in 72 (1 homozygous) of 25790 chromosomes (freq: 0.003); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Ser1691 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 the variant Arg impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.081	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0084	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.69	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.50	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.0010	B;B
Vest4		0.23
MutPred		0.72		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.75
MPC		0.14
ClinPred		0.0040	T
GERP RS		2.6
Varity_R		0.13
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800059; hg19: chr11-108170506; COSMIC: COSV53724445; COSMIC: COSV53724445;