rs3092910

chr11-108310190-T-Cchr11-108310190-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000051.4(ATM):c.5793T>C(p.Ala1931=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00677 in 1,613,558 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (35 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: -0.136

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-108310190-T-C is Benign according to our data. Variant chr11-108310190-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108310190-T-C is described in Lovd as [Likely_benign]. Variant chr11-108310190-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.136 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00604 (920/152308) while in subpopulation EAS AF= 0.0106 (55/5184). AF 95% confidence interval is 0.00837. There are 6 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5793T>C	p.Ala1931=	synonymous_variant	39/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5793T>C	p.Ala1931=	synonymous_variant	39/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 921 AN: 152190 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00506 AC: 1271 AN: 251034 Hom.: 4 AF XY: 0.00488 AC XY: 663 AN XY: 135732

Gnomad AFR exome AF: 0.00790

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0114

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00685 AC: 10005 AN: 1461250 Hom.: 35 Cov.: 31 AF XY: 0.00664 AC XY: 4825 AN XY: 726946

Gnomad4 AFR exome AF: 0.00768

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.00702

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.000600

Gnomad4 NFE exome AF: 0.00773

Gnomad4 OTH exome AF: 0.00893

GnomAD4 genome AF: 0.00604 AC: 920 AN: 152308 Hom.: 6 Cov.: 32 AF XY: 0.00565 AC XY: 421 AN XY: 74484

Gnomad4 AFR AF: 0.00789

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00657

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00552 Hom.: 1

Bravo AF: 0.00634

Asia WGS AF: 0.00927 AC: 32 AN: 3468

EpiCase AF: 0.00698

EpiControl AF: 0.00421

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent variant not near splice site -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ATM: BP4, BP7, BS1, BS2; C11orf65: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Ataxia-telangiectasia syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 10, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 04, 2015	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. -

ATM-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Ala1931= variant was identified in 3 of 572 proband chromosomes (frequency: 0.005) from North American caucasian and American Indian individuals or families with Non-Hodgkin’s Lymphoma, or undisclosed cancer; and was present in 1 of 186 control chromosomes (frequency: 0.005) from healthy individuals (Sipahimalani 2007, Petereit 2013, Thorstenson 2001). Thorstenson et al (2001) showed that ATM shows overall low sequence diversity, when compared across 7 major human populations. The variant was also identified in dbSNP (ID: rs3092910) “With other allele”, ClinVar (classified as benign by Invitae, GeneDx, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Color Genomics Inc; and likely benign by Ambry Genetics, Prevention Genetics, Praxis fuer Humangenetik Tuebingen, Lab. for Molecular Medicine Partners HealthCare Personalized Medicine, and Genetic Services Laboratory (U of Chicago)), Clinvitae (5x), and was not identified in Genesight-COGR, Cosmic, MutDB, LOVD 3.0, and ATM-LOVD. The variant was identified in control databases in 1400 (6 homozygous) of 276860 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 191 (1 homozygous) of 24012 chromosomes (frequency: 008), Other in 27 of 6450 chromosomes (frequency: 004), Latino in 45 of 34376 chromosomes (frequency: 001), European Non-Finnish in 828 (3 homozygous) of 126508 chromosomes (frequency: 007), Ashkenazi Jewish in 31 of 10146 chromosomes (frequency: 003), East Asian in 213 (2 homozygous) of 18848 chromosomes (frequency: 01), European Finnish in 20 of 25750 chromosomes (frequency: 0008), and South Asian in 45 of 30770 chromosomes (frequency: 001). The p.Ala1931= 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 this variant meets our laboratory's criteria to be classified as benign. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

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	-0.50
Cadd	Benign	6.9
Dann	Benign	0.85

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: rs3092910; hg19: chr11-108180917; COSMIC: COSV53762748;