chr11-108223106-G-A

Variant names:

• chr11-108223106-G-A
• rs189037
• ENST00000527805.6:n.-111G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.-111G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 180,500 control chromosomes in the GnomAD database, including 24,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (20089 hom., cov: 32)
  • Exomes 𝑓: 0.52 (4049 hom.)
• Consequence: ATM NM_000051.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.618
• Publications: 116 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-108223106-G-A is Benign according to our data. Variant chr11-108223106-G-A is described in ClinVar as [Benign]. Clinvar id is 302240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.-111G>A		5_prime_UTR_variant	Exon 1 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.-111G>A		5_prime_UTR_variant	Exon 1 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74964 AN: 151940 Hom.: 20079 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.732

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.539

GnomAD4 exome AF: 0.515 AC: 14650 AN: 28442 Hom.: 4049 Cov.: 0 AF XY: 0.523 AC XY: 8065 AN XY: 15418

African (AFR) AF: 0.204 AC: 92 AN: 452

American (AMR) AF: 0.615 AC: 1771 AN: 2880

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 173 AN: 318

East Asian (EAS) AF: 0.384 AC: 527 AN: 1372

South Asian (SAS) AF: 0.555 AC: 3127 AN: 5636

European-Finnish (FIN) AF: 0.507 AC: 355 AN: 700

Middle Eastern (MID) AF: 0.633 AC: 38 AN: 60

European-Non Finnish (NFE) AF: 0.502 AC: 7850 AN: 15624

Other (OTH) AF: 0.512 AC: 717 AN: 1400

GnomAD4 genome AF: 0.493 AC: 74993 AN: 152058 Hom.: 20089 Cov.: 32 AF XY: 0.502 AC XY: 37304 AN XY: 74322

African (AFR) AF: 0.269 AC: 11175 AN: 41488

American (AMR) AF: 0.610 AC: 9318 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2224 AN: 3466

East Asian (EAS) AF: 0.423 AC: 2180 AN: 5158

South Asian (SAS) AF: 0.601 AC: 2896 AN: 4822

European-Finnish (FIN) AF: 0.630 AC: 6661 AN: 10570

Middle Eastern (MID) AF: 0.723 AC: 211 AN: 292

European-Non Finnish (NFE) AF: 0.568 AC: 38601 AN: 67964

Other (OTH) AF: 0.540 AC: 1142 AN: 2116

Alfa AF: 0.433 Hom.: 3760

Bravo AF: 0.480

Asia WGS AF: 0.534 AC: 1854 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20816691, 22529920, 22960875, 20004998, 21108427, 23993922, 21937043) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.8
DANN	Benign	0.96
PhyloP100		0.62
PromoterAI		-0.044	Neutral
Mutation Taster		=293/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs189037; hg19: chr11-108093833; COSMIC: COSV53716927; COSMIC: COSV53716927;