11-108280980-TA-TAA

Variant names:

• chr11-108280980-T-TA
• rs3218681
• NM_000051.4:c.3403-13dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.3403-13dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,555,222 control chromosomes in the GnomAD database, including 239,756 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.55 (23487 hom., cov: 0)
  • Exomes 𝑓: 0.56 (216269 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.133
• Publications: 16 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):

• ATM-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary breast carcinoma

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

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

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

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 11-108280980-T-TA is Benign according to our data. Variant chr11-108280980-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 181858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.3403-13dupA		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.3403-13dupA		intron	N/A	NP_001338763.1	Q13315

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.3403-15_3403-14insA		intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.3403-15_3403-14insA		intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.3403-15_3403-14insA		intron	N/A	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83626 AN: 151636 Hom.: 23475 Cov.: 0

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.582

GnomAD2 exomes AF: 0.560 AC: 129971 AN: 231976 AF XY: 0.565

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.611

Gnomad ASJ exome AF: 0.611

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.612

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.557 AC: 782075 AN: 1403468 Hom.: 216269 Cov.: 31 AF XY: 0.561 AC XY: 392636 AN XY: 699554

African (AFR) AF: 0.444 AC: 13993 AN: 31526

American (AMR) AF: 0.612 AC: 25507 AN: 41652

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 15408 AN: 25092

East Asian (EAS) AF: 0.396 AC: 15534 AN: 39220

South Asian (SAS) AF: 0.624 AC: 50718 AN: 81228

European-Finnish (FIN) AF: 0.615 AC: 31820 AN: 51714

Middle Eastern (MID) AF: 0.718 AC: 3972 AN: 5530

European-Non Finnish (NFE) AF: 0.554 AC: 592512 AN: 1069350

Other (OTH) AF: 0.561 AC: 32611 AN: 58156

GnomAD4 genome AF: 0.551 AC: 83667 AN: 151754 Hom.: 23487 Cov.: 0 AF XY: 0.558 AC XY: 41377 AN XY: 74200

African (AFR) AF: 0.460 AC: 19045 AN: 41358

American (AMR) AF: 0.627 AC: 9557 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2275 AN: 3472

East Asian (EAS) AF: 0.395 AC: 2047 AN: 5178

South Asian (SAS) AF: 0.644 AC: 3097 AN: 4812

European-Finnish (FIN) AF: 0.628 AC: 6589 AN: 10494

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39006 AN: 67888

Other (OTH) AF: 0.583 AC: 1227 AN: 2106

Alfa AF: 0.539 Hom.: 3337

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Ataxia-telangiectasia syndrome (3)
-	-	2	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3218681; hg19: chr11-108151707; COSMIC: COSV53729230;