rs1800060

chr11-108317409-G-Achr11-108317409-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):c.6235G>A(p.Val2079Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,611,760 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2079A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0059 (9 hom., cov: 28)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23 O:1
• Conservation: PhyloP100: -0.0380

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008029282).
• BP6: Variant 11-108317409-G-A is Benign according to our data. Variant chr11-108317409-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108317409-G-A is described in Lovd as [Benign]. Variant chr11-108317409-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00592 (897/151400) while in subpopulation AFR AF= 0.0174 (718/41218). AF 95% confidence interval is 0.0164. There are 9 homozygotes in gnomad4. There are 414 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.6235G>A	p.Val2079Ile	missense_variant	43/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.6235G>A	p.Val2079Ile	missense_variant	43/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 898 AN: 151284 Hom.: 9 Cov.: 28

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00508

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.0000961

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.00530

GnomAD3 exomes AF: 0.00252 AC: 634 AN: 251386 Hom.: 5 AF XY: 0.00202 AC XY: 275 AN XY: 135868

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000748

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00128 AC: 1864 AN: 1460360 Hom.: 7 Cov.: 30 AF XY: 0.00120 AC XY: 875 AN XY: 726554

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000462

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.00592 AC: 897 AN: 151400 Hom.: 9 Cov.: 28 AF XY: 0.00560 AC XY: 414 AN XY: 73910

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.00507

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.0000961

Gnomad4 NFE AF: 0.000589

Gnomad4 OTH AF: 0.00525

Alfa AF: 0.00304 Hom.: 4

Bravo AF: 0.00731

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00257 AC: 312

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8 Other:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Ataxia-telangiectasia syndrome Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2016	- -
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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jun 18, 2017	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 14, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 29, 2021

- -

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.Val2079Ile variant was identified in 9 of 9208 proband chromosomes (frequency: 0.00119) from individuals or families with breast cancer, Hodgkin’s disease and was present in 6 of 852 control chromosomes (frequency: 0.007) from healthy individuals (Bretsky 2003, Offit 2002, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs1800060) as With Benign allele, ClinVar (classified as benign by GeneDx, Ambry genetics, Invitae, PreventionGenetics), MutDB (classified as polymorphism), databases. The variant was not identified in Cosmic, LOVD 3.0, ATM-LOVD, databases. The variant was identified in control databases in 779(8 homozygous) of 276904 chromosomes at a frequency of 0.0028 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 426 of 23972 chromosomes (freq: 0.018), Ashkenazi Jewish* in 143 of 10150 chromosomes (freq: 0.014). The p.Val2079 residue is not conserved in mammals and 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the PIK-related kinase Armadillo-type fold functional domain increasing the likelihood that it may have clinical significance. 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

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
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.0050
Dann	Benign	0.62
DEOGEN2	Benign	0.059	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.40	T;.
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.078
Sift	Benign	0.40	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0020	B;B
Vest4		0.10
MVP		0.44
MPC		0.099
ClinPred		0.0056	T
GERP RS		-12
Varity_R		0.038
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1800060; hg19: chr11-108188136; COSMIC: COSV53744931; COSMIC: COSV53744931;