11-108326169-C-T

Position:

chr11-108326169-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000051.4(ATM):c.6919C>T(p.Leu2307Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000745 in 1,614,026 control chromosomes in the GnomAD database, including 13 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 0.00083 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 11 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:25O:1

Conservation

PhyloP100: 3.77

Variant links:

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 links:

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]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013343096).

BP6

Variant 11-108326169-C-T is Benign according to our data. Variant chr11-108326169-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127430.We mark this variant Likely_benign, oryginal submissions are: {Benign=11, Uncertain_significance=2, Likely_benign=4, not_provided=1}. Variant chr11-108326169-C-T is described in Lovd as [Benign]. Variant chr11-108326169-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.6919C>T	p.Leu2307Phe	missense_variant	47/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.6919C>T	p.Leu2307Phe	missense_variant	47/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.000828

AC:

126

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00141

AC:

355

AN:

251346

Hom.:

AF XY:

0.00133

AC XY:

180

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.0304

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.000736

AC:

1076

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000780

AC XY:

567

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0303

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000139

Gnomad4 OTH exome

AF:

0.00207

GnomAD4 genome

AF:

0.000828

AC:

126

AN:

152174

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.0294

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.00159

Hom.:

Bravo

AF:

0.000790

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00110

AC:

134

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:25Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2015	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely 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, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 26, 2017	- -

not provided

Uncertain:1Benign:6

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ATM: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 17, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 03, 2017	Variant summary: This c.6919C>T variant affects a conserved nucleotide, resulting in conservative amino acid change from Leu to Phe. 3/5 in-silico tools predict this variant to be damaging. This variant has been reported in patients with breast cancer, ovarian cancer, melanoma, lung cancer, CLL or Hodgkin's disease; however, without evidence on co-segregation analysis. In one family with familial CLL, this variant was found in one affected brother but not in the other affected brother (Yuille_2002) (ACMG, BS4). Additionally, in a patient with a history of Lynch syndrome, the variant co-occurred with a pathogenic MSH2 variant (Yurgelun_2015) (ACMG, BP5). This variant has not been reported in patients with Ataxia-Telangiectasia (a recessive disorder). This variant was found in 140/128300 control chromosomes including one homozygote (ACMG, BS2) from multiple ethnic populations at a frequency of 0.0010912, which is about 2 times greater than the maximal expected frequency of a pathogenic allele (0.0005001) in this gene, suggesting this variant is benign (ACMG, BS1). Multiple case-control studies have shown that this variant was not associated with breast cancer, except one study (Haiman_2013, OR=4.133 in mixed ethnic populations, OR=9.805 in European American). The study (Haiman_2013), however, did not provide confidence interval and distribution of the variant is patient and control cohorts appear to be small, not suggesting a believable odds ratio. Multiple clinical laboratories classified this variant as likely benign/benign (ACMG BP6). Taken together, this variant was classified as a Benign variant. -

Hereditary cancer-predisposing syndrome

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 08, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 28, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 12, 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	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 22, 2022	- -

Ataxia-telangiectasia syndrome

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 26, 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.Leu2307Phe variant was identified in 18 of 2820 proband chromosomes (frequency: 0.006) from British, Brazilian, French, Dutch and American individuals or families with chronic lymphocytic leukemia or breast cancer (Yuille 2002, LâˆšÂ§hdesmâˆšÂ§ki 2004, Tiao 2017, Mangone 2015, Broeks 2008, LaPaglia 2010). The variant was also identified in the following databases: dbSNP (ID: rs56009889) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar and Clinvitae (3x classified as benign by GeneDx, Invitae, Ambry Genetics; 1x classified as uncertain significance by EGL Genetic Diagnostics; 1x classification not provided by ITMI), and COSMIC (1x confirmed somatic in hemangioblastoma). The variant was not identified in GeneInsight-COGR, MutDB, LOVD 3.0, or the ATM-LOVD databases. The variant was identified in control databases in 356 of 277088 chromosomes (3 homozygous) at a frequency of 0.001 in the following populations: Ashkenazi Jewish in 310 of 10148 chromosomes (freq 0.03); population classified as â€šÃ„Ãºotherâ€šÃ„Ã¹ in 9 of 6458 chromosomes (freq 0.001); European non-Finnish in 32 of 126602 chromosomes (freq 0.0002); Latino in 3 of 34416 chromosomes (freq 0.00009); African in 2 of 24036 chromosomes (freq 0.00008) increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In a study of Brazilian patients with sporadic breast cancer this variant was found in two patients, one of who also harboured a second ATM variant (p.Thr935Arg) and demonstrated loss of heterozygosity in tumour DNA (Mangone 2015). This variant was found together with an inactivating BRCA2 nonsense variant in a prostate cancer patient with exceptional response to high-dose testosterone therapy (Tepley 2017). The p.Leu2307Phe variant has also been reported in a French breast cancer patient with a family history of both breast cancer and hematological malignancy (LaPaglia 2010). In a study of ATM mutations in European familial chronic lymphocytic leukemia patients this variant was found in one patient but not in a brother with disease (Yuille 2002). The p.Leu2307Phe residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;.

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

1.0

D;D

Vest4

0.51

MVP

0.91

MPC

0.59

ClinPred

0.11

GERP RS

5.6

Varity_R

0.62

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over