11-108326169-C-T

Variant names:

• chr11-108326169-C-T
• rs56009889
• NM_000051.4:c.6919C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:25 O:1
• Conservation: PhyloP100: 3.77

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 -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: {Likely_benign=4, Benign=11, Uncertain_significance=2, 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 rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.6919C>T	p.Leu2307Phe	missense_variant	Exon 47 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6919C>T	p.Leu2307Phe	missense_variant	Exon 47 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152174 Hom.: 2 Cov.: 32

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.: 2 AF XY: 0.00133 AC XY: 180 AN XY: 135842

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.: 11 Cov.: 32 AF XY: 0.000780 AC XY: 567 AN XY: 727226

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.: 2 Cov.: 32 AF XY: 0.000686 AC XY: 51 AN XY: 74338

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.: 2

Bravo AF: 0.000790

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00110 AC: 134

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:10 Other:1

Nov 11, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 26, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.6919C>T (p.Leu2307Phe) results in a non-conservative amino acid change located in the FAT domain profile (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 258272 control chromosomes, predominantly at a frequency of 0.03 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 30-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting the variant is benign. Additionally, the variant was found in 25 individuals in the FLOSSIES database (women aged 70+ without history of cancer) at a frequency of 0.00253, providing additional evidence the variant is benign. c.6919C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer, melanoma, lung cancer, CLL or Hodgkin's disease; however, without evidence of co-segregation with disease and with additional case-control studies showing the variant was not associated with breast cancer. Additionally, in a patient with a history of Lynch syndrome, the variant co-occurred with a pathogenic MSH2 variant (Yurgelun_2015). This variant has not been reported in patients with Ataxia-Telangiectasia. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g. Shankar_2014). The following publications have been ascertained in the context of this evaluation (PMID: 17344846, 23555315, 24728327, 24448499, 24326041, 19404735, 11505391, 25625042, 17393301, 21787400, 19781682, 20305132, 25589003, 12473594, 22369572, 24628946, 14754616, 12091354). ClinVar contains an entry for this variant (Variation ID: 127430). Based on the evidence outlined above, the variant was classified as benign. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2019

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:5

Aug 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BS1, BS4 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 13, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 20, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5

Jul 12, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 08, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 11, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 22, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Apr 26, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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, Lähdesmäki 2004, Tiao 2017, Mangone 2015, Broeks 2008, LaPaglia 2010). The variant was also identified in the following databases: dbSNP (ID: rs56009889) as “With other allele”, 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 “other” 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	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;.
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.59	T
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	T
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

Other links and lift over

dbSNP: rs56009889; hg19: chr11-108196896; COSMIC: COSV53758041; COSMIC: COSV53758041;