chr11-108332045-G-T

Variant names:

• chr11-108332045-G-T
• rs112775908
• NM_000051.4:c.7788+8G>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):​c.7788+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,613,304 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001647
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:31
• Conservation: PhyloP100: 0.0870

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-108332045-G-T is Benign according to our data. Variant chr11-108332045-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127450.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Benign=9, Uncertain_significance=1}. Variant chr11-108332045-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00166 (252/152242) while in subpopulation NFE AF= 0.00304 (207/68010). AF 95% confidence interval is 0.0027. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.7788+8G>T		splice_region_variant, intron_variant	Intron 52 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7788+8G>T		splice_region_variant, intron_variant	Intron 52 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 152124 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00147 AC: 368 AN: 250684 Hom.: 0 AF XY: 0.00151 AC XY: 204 AN XY: 135508

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00282 AC: 4125 AN: 1461062 Hom.: 9 Cov.: 31 AF XY: 0.00272 AC XY: 1975 AN XY: 726808

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00347

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00166 AC: 252 AN: 152242 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74432

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00304

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00153

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:31

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:12

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 09, 2017

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

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

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 22, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 17, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BP4, BS2 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely 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

- -

Apr 13, 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. -

Feb 15, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:4

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 30, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5

Sep 15, 2021

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Aug 07, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 21, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Familial cancer of breast Benign:2

Jun 17, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. 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]. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

May 23, 2023

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

Significance: Likely 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

ATM, EXON52, c.7788+8G>T, r.(spl)?, Heterozygous, Likely Benign The ATM c.7788+8G>T variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in the following databases: dbSNP (ID: rs112775908) as “With other allele”, ClinVar (as likely benign by ARUP Laboratories and PreventionGenetics, and as benign by GeneDx and Invitae), Clinvitae (as likely benign and benign). The variant was identified in control databases in 404 of 276410 chromosomes (1 homozygous) at a frequency of 0.001462 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 7 of 24012 chromosomes (freq: 0.000292), Other in 4 of 6446 chromosomes (freq: 0.000621), Latino in 18 of 34394 chromosomes (freq: 0.000523), European (Non-Finnish) in 355 (1 homozygous) of 126082 chromosomes (freq: 0.002816), Ashkenazi Jewish in 11 of 10126 chromosomes (freq: 0.001086), and European (Finnish) in 9 of 25766 chromosomes (freq: 0.000349), while the variant was not observed in the East Asian and South Asian populations. 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
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.5
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs112775908; hg19: chr11-108202772; COSMIC: COSV104592037; COSMIC: COSV104592037;