11-108244860-C-T

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.735C>T(p.Val245=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,613,792 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V245V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 31)
  • Exomes 𝑓: 0.012 (169 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -0.447

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-108244860-C-T is Benign according to our data. Variant chr11-108244860-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 183707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108244860-C-T is described in Lovd as [Benign]. Variant chr11-108244860-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.447 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0103 (1568/152198) while in subpopulation NFE AF= 0.0136 (923/68010). AF 95% confidence interval is 0.0128. There are 16 homozygotes in gnomad4. There are 835 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.735C>T	p.Val245=	synonymous_variant	7/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.735C>T	p.Val245=	synonymous_variant	7/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1568 AN: 152080 Hom.: 16 Cov.: 31

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0460

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.0113 AC: 2829 AN: 251032 Hom.: 41 AF XY: 0.0113 AC XY: 1530 AN XY: 135672

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0417

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.00932

GnomAD4 exome AF: 0.0125 AC: 18238 AN: 1461594 Hom.: 169 Cov.: 32 AF XY: 0.0122 AC XY: 8866 AN XY: 727096

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000672

Gnomad4 FIN exome AF: 0.0415

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.00898

GnomAD4 genome AF: 0.0103 AC: 1568 AN: 152198 Hom.: 16 Cov.: 31 AF XY: 0.0112 AC XY: 835 AN XY: 74406

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0460

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.0111 Hom.: 20

Bravo AF: 0.00701

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.0107

EpiControl AF: 0.0119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Ataxia-telangiectasia syndrome Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Aug 23, 2016	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ATM: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 12810666) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 26, 2017	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 06, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 01, 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	Color Diagnostics, LLC DBA Color Health	Apr 02, 2015	- -

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.Val245= variant was identified in 44 of 3228 proband chromosomes (frequency: 0.01) from individuals or families with b-cell lymphoma tumours, chronic lymphocytic leukemia and hereditary breast and ovarian cancer and was present in 74 of 4368 control chromosomes (frequency: 0.007) from healthy individuals (Skowronska 2012, Concannon 2008, Gronbaek 2002, Heikkinen 2005, Mangone 2015, Petereit 2013, Tommiska 2006). The variant was identified in dbSNP (rs3218674) as “with likely benign, other allele, ClinVar (classified as benign by Invitae, Ambry Genetics, Color, PreventionGenetics and 2 other submitters and likely benign by True Health Diagnostics, Illumina and Counsyl) and LOVD 3.0 (observed 5x). The variant was identified in control databases in 3269 of 282,410 chromosomes (43 homozygous) at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Finnish in 1057 of 25,098 chromosomes (freq: 0.04), European in 1977 of 128,822 chromosomes (freq: 0.02), Other in 78 of 7206 chromosomes (freq: 0.01), Latino in 100 of 35,408 chromosomes (freq: 0.003), African in 45 of 24,960 chromosomes (freq: 0.002), South Asian in 10 of 30,610 chromosomes (freq: 0.0003), Ahkenazi Jewish in 2 of 10,360 chromosomes (freq: 0.0002), while the variant was not observed in the East Asian population. The p.Val245= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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	-0.56
Cadd	Benign	5.8
Dann	Benign	0.65
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: rs3218674; hg19: chr11-108115587; COSMIC: COSV53775314; COSMIC: COSV53775314;