11-108292655-C-T

Position:

• chr11-108292655-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000051.4(ATM):​c.4473C>T​(p.Phe1491Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,613,764 control chromosomes in the GnomAD database, including 3 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 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:28
• Conservation: PhyloP100: 0.0960

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 11-108292655-C-T is Benign according to our data. Variant chr11-108292655-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135754.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=1, Benign=8}. Variant chr11-108292655-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.096 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00184 (2692/1461724) while in subpopulation NFE AF= 0.0022 (2448/1111930). AF 95% confidence interval is 0.00213. There are 2 homozygotes in gnomad4_exome. There are 1326 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• 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	c.4473C>T	p.Phe1491Phe	synonymous_variant	30/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4473C>T	p.Phe1491Phe	synonymous_variant	30/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 151926 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000854

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000758

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00122 AC: 306 AN: 251318 Hom.: 0 AF XY: 0.00128 AC XY: 174 AN XY: 135826

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00184 AC: 2692 AN: 1461724 Hom.: 2 Cov.: 31 AF XY: 0.00182 AC XY: 1326 AN XY: 727158

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00220

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152040 Hom.: 1 Cov.: 32 AF XY: 0.00104 AC XY: 77 AN XY: 74296

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000853

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000758

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00117

EpiCase AF: 0.00235

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:28

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:10

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ATM: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 15, 2017	- -
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	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 12, 2019	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 05, 2020	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Mar 23, 2017	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 10, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2016	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, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 13, 2021	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 22, 2021	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.4473C>T, in exon 30 which does not result in an amino acid change. This sequence change has been described in the gnomAD database with a frequency of 0.20% in the European sub-population (dbSNP rs4988008). The p.Phe1491Phe change has been identified in a hereditary breast and ovarian cancer family (PMID: 12810666). This sequence change is not predicted to have a deleterious effect on splicing based on in silico splice prediction programs. The p.Phe1491Phe change affects a moderately conserved nucleotide located in a domain of the ATM protein that is not known to be functional. It is likely that this is a normal variant in the ATM gene however functional studies have not been performed to prove this conclusively. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 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. -

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

Mar 23, 2023

- -

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.Phe1491= variant was identified in 1 of 1010 proband chromosomes (frequency: 0.001) from individuals or families with prostate cancer, breast cancer or chronic lymphocytic leukemia, and was present in 6 of 1439 control chromosomes (freq. 0.004) from healthy individuals (Skowronska_2011_21933854, Stock_2013_NA, Rosentein_2006_NA). The variant was also identified in dbSNP (ID: rs4988008) as “With other allele”, Clinvar and Clinvitae (3x classified as benign by Invitae, GeneDx, Color Genomics; 1x classified as likely benign by Ambry Genetics; 1x classified as uncertain significance by Illumina), COSMIC (1x in acute myeloid leukemia, somatic status unconfirmed), and LOVD 3.0 (2 entries, not classified) databases. The variant was not identified in the GeneInsight-COGR or MutDB databases. The variant was identified in control databases in 333 of 277018 chromosomes (0 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 6 of 24020 chromosomes (freq: 0.0002), Other in 9 of 6456 chromosomes (freq: 0.001), Latino in 21 of 34412 chromosomes (freq: 0.0006), European Non-Finnish in 262 of 126558 chromosomes (freq: 0.002), Ashkenazi Jewish in 22 of 10150 chromosomes (freq: 0.002), European Finnish in 13 of 25778 chromosomes (freq: 0.0005) while the variant was not observed in the East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational predictions software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Phe1491= 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 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. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 20, 2024

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely 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	-0.24
CADD	Benign	7.6
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs4988008; hg19: chr11-108163382; COSMIC: COSV53736533; COSMIC: COSV53736533;