rs672655

Variant names:

• chr11-108258930-A-G
• rs672655
• NM_000051.4:c.2377-56A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108258930-A-G
• chr11-108258930-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.2377-56A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,410,390 control chromosomes in the GnomAD database, including 217,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (20115 hom., cov: 32)
  • Exomes 𝑓: 0.56 (197198 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.18
• Publications: 25 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 11-108258930-A-G is Benign according to our data. Variant chr11-108258930-A-G is described in ClinVar as Benign. ClinVar VariationId is 1177614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2377-56A>G		intron_variant	Intron 15 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2377-56A>G		intron_variant	Intron 15 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75137 AN: 151940 Hom.: 20105 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.538

GnomAD4 exome AF: 0.556 AC: 699635 AN: 1258332 Hom.: 197198 AF XY: 0.560 AC XY: 355690 AN XY: 635680

African (AFR) AF: 0.268 AC: 7912 AN: 29520

American (AMR) AF: 0.629 AC: 27221 AN: 43278

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 15130 AN: 24720

East Asian (EAS) AF: 0.430 AC: 16587 AN: 38534

South Asian (SAS) AF: 0.597 AC: 48513 AN: 81196

European-Finnish (FIN) AF: 0.627 AC: 32258 AN: 51488

Middle Eastern (MID) AF: 0.715 AC: 3795 AN: 5306

European-Non Finnish (NFE) AF: 0.557 AC: 518891 AN: 930824

Other (OTH) AF: 0.549 AC: 29328 AN: 53466

GnomAD4 genome AF: 0.494 AC: 75167 AN: 152058 Hom.: 20115 Cov.: 32 AF XY: 0.503 AC XY: 37388 AN XY: 74342

African (AFR) AF: 0.276 AC: 11446 AN: 41480

American (AMR) AF: 0.607 AC: 9260 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2220 AN: 3468

East Asian (EAS) AF: 0.421 AC: 2179 AN: 5180

South Asian (SAS) AF: 0.604 AC: 2912 AN: 4822

European-Finnish (FIN) AF: 0.629 AC: 6641 AN: 10562

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.567 AC: 38556 AN: 67970

Other (OTH) AF: 0.539 AC: 1139 AN: 2112

Alfa AF: 0.503 Hom.: 3022

Bravo AF: 0.481

Asia WGS AF: 0.531 AC: 1844 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 63% of patients studied by a panel of primary immunodeficiencies. Number of patients: 60. Only high quality variants are reported. -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Ataxia-telangiectasia syndrome Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		2.2
Mutation Taster		=100/0	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: rs672655; hg19: chr11-108129657; COSMIC: COSV53757995; COSMIC: COSV53757995;