11-108227865-T-C

Position:

• chr11-108227865-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000051.4(ATM):​c.162T>C​(p.Tyr54=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,613,016 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:30
• Conservation: PhyloP100: -1.85

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 11-108227865-T-C is Benign according to our data. Variant chr11-108227865-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132757.We mark this variant Likely_benign, oryginal submissions are: {Benign=11, Likely_benign=10, Uncertain_significance=1}. Variant chr11-108227865-T-C is described in Lovd as [Benign]. Variant chr11-108227865-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (299/152336) while in subpopulation NFE AF= 0.00348 (237/68020). AF 95% confidence interval is 0.00312. There are 1 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.162T>C	p.Tyr54=	synonymous_variant	3/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.162T>C	p.Tyr54=	synonymous_variant	3/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00173 AC: 433 AN: 250966 Hom.: 0 AF XY: 0.00189 AC XY: 256 AN XY: 135674

Gnomad AFR exome AF: 0.000742

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000689

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00278

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00267 AC: 3903 AN: 1460680 Hom.: 6 Cov.: 31 AF XY: 0.00260 AC XY: 1887 AN XY: 726590

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00257

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000686

Gnomad4 FIN exome AF: 0.00206

Gnomad4 NFE exome AF: 0.00315

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74504

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00348

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00258 Hom.: 1

Bravo AF: 0.00172

Asia WGS AF: 0.000867 AC: 3 AN: 3474

EpiCase AF: 0.00338

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:30

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:9

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2016	Variant summary: This c.162T>C variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 208/121226 control chromosomes (including the large and broad populations of ExAC) at a frequency of 0.0017158, which does not exceed the maximal expected frequency of a pathogenic allele (0.0039528) in this gene. However, the possibility that this variant can still represents as a rare polymorphism cannot be ruled out from the comparison. The variant is more common in European (Non-Finnish) population where its allele frequency is 0.25% (167/66625 chromosomes) including one homozygous occurrence. The homozygote is suggestive of a benign outcome with respect to early onset recessive phenotype A-T. [Penetrance of variants causing A-T is not exactly known.] This variant has been found in patients with A-T, breast and/or ovarian cancer, chronic lymphocytic leukemia and Hodgkins lymphoma. The publications reporting patient occurrences report this variant as polymorphism. In one A-T patient reported, the patient also carried other two potentially pathogenic variants (Buzin_2003), suggesting a benign outcome for this variant. In addition, this variant was found at similar frequencies in a small case-control study (Liberzon_2004), further supporting a benign outcome. Multiple clinical labs have classified this variant as benign/likely benign. Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 21, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Tyr54= variant was identified in 8 of 1966 proband chromosomes (frequency: 0.004) from Finnish, Dutch and Austrian individuals or families with (BRCA1/2 negative) breast cancer or HBOC, American/non America Indian individuals undergoing radiation therapy, and Jewish children with Hodgkin’s disease (Tommiska_2006_16914028, Thorstenson_2003_12810666, Petereit_2013_24416720, Liberzon_2004_14735203, Broeks_2008_17393301). The variant was identified in dbSNP (ID: rs3218690) “With other allele”, ClinVar (conflicting interpretations of pathogenicity; submitters: benign by Invitae and GeneDx, likely benign by Ambry Genetics and Genetic Services Laboratory (University of Chicago), and uncertain significance by Praxis fur Humangenetik Tuebingen), Clinvitae (4x), and was not identified in GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0. The variant was also identified in control databases in 486 (1 homozygous) of 276848 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 14 of 24010 chromosomes (freq: 0.0006), Other in 13 of 6460 chromosomes (freq: 0.002), Latino in 12 of 34408 chromosomes (freq: 0.0003), European Non-Finnish in 359 (1 homozygous) of 126590 chromosomes (freq: 0.003), Ashkenazi Jewish in 24 of 10142 chromosomes (freq: 0.002), European Finnish in 43 of 25762 chromosomes (freq: 0.002), and South Asian in 21 of 30610 chromosomes (freq: 0.0007) while not observed in the East Asian population. The p.Tyr54= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ATM: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 07, 2022	- -

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 11, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
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. -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 25, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 03, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 20, 2014	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	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.162T>C p.(Tyr54=) variant has an allele frequency of 0.00283 (0.23%, 334/ 118012 alleles) in the Non-Finnish European population of the gnomAD v2.1.1 non-cancer dataset (BS1; http://gnomad.broadinstitute.org). It is a silent variant not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike – MaxEntScan – NNSplice - GeneSplicer (BP4). The variant is located at a nucleotide that is not highly conserved across species, based on PhyloP (BP7). This silent variant has been identified in two ataxia telangiectasia patients, but in one case there were also detected two (likely) pathogenic variants (PMID: 12552559) and in the other one, there was also detected an homozygous truncating variant (PMID: 28898322). This, together with the high frequency of the variant in the general population suggests that c.162T>C was just a coincident polymorphism and discards the use of PM3 and PS4 criteria. Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BP4 + BP7 (PMID: 33280026). -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 17, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 23, 2022

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.92
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs3218690; hg19: chr11-108098592; COSMIC: COSV104592234; COSMIC: COSV104592234;