11-108250683-CTTTTTTT-CTTTTT

Variant names:

• chr11-108250683-CTT-C
• rs34325032
• NM_000051.4:c.1236-4_1236-3delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000051.4(ATM):​c.1236-4_1236-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,476,638 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0050 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.211
• Publications: 10 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 -8 ACMG points.

• BP6: Variant 11-108250683-CTT-C is Benign according to our data. Variant chr11-108250683-CTT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1209911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1236-4_1236-3delTT		splice_region intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.1236-4_1236-3delTT		splice_region 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.1236-17_1236-16delTT		intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.1236-17_1236-16delTT		intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.1236-17_1236-16delTT		intron	N/A	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.000218 AC: 31 AN: 142218 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000779

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000701

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000204

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000259

Gnomad OTH AF: 0.000514

GnomAD2 exomes AF: 0.00999 AC: 1632 AN: 163404 AF XY: 0.0101

Gnomad AFR exome AF: 0.00764

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.00898

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.00970

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00498 AC: 6646 AN: 1334404 Hom.: 0 AF XY: 0.00493 AC XY: 3278 AN XY: 665096

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00690 AC: 207 AN: 29998

American (AMR) AF: 0.00854 AC: 326 AN: 38180

Ashkenazi Jewish (ASJ) AF: 0.00618 AC: 148 AN: 23930

East Asian (EAS) AF: 0.00470 AC: 176 AN: 37440

South Asian (SAS) AF: 0.00564 AC: 438 AN: 77644

European-Finnish (FIN) AF: 0.00517 AC: 196 AN: 37890

Middle Eastern (MID) AF: 0.00262 AC: 12 AN: 4578

European-Non Finnish (NFE) AF: 0.00473 AC: 4869 AN: 1029250

Other (OTH) AF: 0.00494 AC: 274 AN: 55494

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000218 AC: 31 AN: 142234 Hom.: 0 Cov.: 0 AF XY: 0.000263 AC XY: 18 AN XY: 68550

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000777 AC: 3 AN: 38604

American (AMR) AF: 0.0000701 AC: 1 AN: 14268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4890

South Asian (SAS) AF: 0.00 AC: 0 AN: 4506

European-Finnish (FIN) AF: 0.00101 AC: 8 AN: 7956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000260 AC: 17 AN: 65500

Other (OTH) AF: 0.000512 AC: 1 AN: 1952

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0123 Hom.: 575

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial colorectal cancer type X (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34325032; hg19: chr11-108121410;