11-108254034-T-C

Position:

• chr11-108254034-T-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.2119T>C​(p.Ser707Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,392 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. S707S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27 O:1
• Conservation: PhyloP100: -0.160

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057876706).
• BP6: Variant 11-108254034-T-C is Benign according to our data. Variant chr11-108254034-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108254034-T-C is described in Lovd as [Benign]. Variant chr11-108254034-T-C is described in Lovd as [Likely_benign]. Variant chr11-108254034-T-C is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00763 (1162/152252) while in subpopulation NFE AF= 0.0119 (809/67998). AF 95% confidence interval is 0.0112. There are 6 homozygotes in gnomad4. There are 560 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2119T>C	p.Ser707Pro	missense_variant	13/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2119T>C	p.Ser707Pro	missense_variant	13/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1163 AN: 152134 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00878

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00796 AC: 1991 AN: 250180 Hom.: 11 AF XY: 0.00820 AC XY: 1110 AN XY: 135394

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.00806

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00510

Gnomad FIN exome AF: 0.00491

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0110 AC: 16108 AN: 1461140 Hom.: 124 Cov.: 30 AF XY: 0.0109 AC XY: 7903 AN XY: 726884

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00651

Gnomad4 ASJ exome AF: 0.00838

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00474

Gnomad4 FIN exome AF: 0.00569

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.00848

GnomAD4 genome AF: 0.00763 AC: 1162 AN: 152252 Hom.: 6 Cov.: 32 AF XY: 0.00752 AC XY: 560 AN XY: 74448

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00877

Gnomad4 ASJ AF: 0.00837

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0115 Hom.: 18

Bravo AF: 0.00796

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.00781 AC: 948

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:27 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9 Other:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Ataxia-telangiectasia syndrome Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
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	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Ser707Pro variant was identified in 542 of 44368 proband chromosomes (frequency: 0.0122) from individuals or families with breast and thyroid cancer and was present in 6 of 1000 control chromosomes (frequency: 0.006) from healthy individuals (Dork 2001, Barbazetto 2008, Dombernowsky 2008, Fletcher 2010, Petereit 2013, Spurdle 2002). The variant was also identified in dbSNP (ID: rs4986761) as other, ClinVar (classified as benign by GeneDx, Ambry genetics, Emory genetics, Color Genomics, Invitae), Cosmic (classified as neutral), MutDB (classified as polymorphism), and LOVD 3.0 databases. The variant was not identified in GeneInsight-COGR and ATM-LOVD databases. The variant was identified in control databases in 2208 of 276136 chromosomes at a frequency of 0.007996 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%: European (Non-Finnish) (6 homozygous) in 1508 of 126110 chromosomes (freq: 0.012), Other in 70 of 6438 chromosomes (freq: 0.011). In one study, the p.Ser707Pro variant appeared to be associated with high-risk breast carcinoma, characterized by a positive axillary nodal status and an increased risk of contralateral breast cancer (Dork, 2001). The p.Ser707Pro variant is likely to interfere with secondary and tertiary protein structure, as the exchange of proline for serine introduces a much bulkier side chain and removes a hydroxyl group that possibly participates in hydrogen bonding (Dork, 2001). However, several large population studies have shown that the variant was not associated with an increased breast cancer risk compared with the general population, or overall cancer risk (Barbazetto 2008, Choi 2016, Fletcher 2010, Spurdle 2002). In addition, in their study Thorstenson (2003) found the variant did not segregate with disease. The p.Ser707Pro residue is not conserved in mammals and mammals and the variant amino acid Proline (Pro) is present in several lower organisms, increasing the likelihood that this variant does not have clinical significance. 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 Armadillo-type fold functional domain(s), the clinical significance of which cannot be determined. 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. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATM: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 04, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
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. -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 07, 2024	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.96
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.56	T;T;.
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.80	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.096, 0.12
MVP		0.74
MPC		0.16
ClinPred		0.0022	T
GERP RS		3.8
Varity_R		0.31
gMVP		0.14

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: rs4986761; hg19: chr11-108124761; COSMIC: COSV53743430; COSMIC: COSV53743430;