chr11-108250683-C-CT

Variant names:

• chr11-108250683-C-CT
• rs34325032
• NM_000051.4:c.1236-3dupT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.1236-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 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 0.54 (20785 hom., cov: 0)
  • Exomes 𝑓: 0.37 (804 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATM NM_000051.4 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.510
• 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 -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.040562645 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 0 (no position change), new splice context is: ccttttttttttttttttAGgct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 11-108250683-C-CT is Benign according to our data. Variant chr11-108250683-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 181847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.633 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.1236-3dupT		splice_acceptor intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.1236-3dupT		splice_acceptor 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.1236-18_1236-17insT		intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.1236-18_1236-17insT		intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.1236-18_1236-17insT		intron	N/A	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.540 AC: 76814 AN: 142254 Hom.: 20790 Cov.: 0

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.777

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.577

GnomAD2 exomes AF: 0.368 AC: 60152 AN: 163404 AF XY: 0.370

Gnomad AFR exome AF: 0.327

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.384

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.385

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.380

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.368 AC: 490593 AN: 1333196 Hom.: 804 Cov.: 0 AF XY: 0.369 AC XY: 244864 AN XY: 664030

African (AFR) AF: 0.296 AC: 8955 AN: 30258

American (AMR) AF: 0.354 AC: 13518 AN: 38206

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 9098 AN: 23888

East Asian (EAS) AF: 0.313 AC: 11725 AN: 37418

South Asian (SAS) AF: 0.386 AC: 29534 AN: 76520

European-Finnish (FIN) AF: 0.364 AC: 13776 AN: 37876

Middle Eastern (MID) AF: 0.398 AC: 1834 AN: 4610

European-Non Finnish (NFE) AF: 0.371 AC: 381896 AN: 1028950

Other (OTH) AF: 0.365 AC: 20257 AN: 55470

GnomAD4 genome AF: 0.540 AC: 76806 AN: 142278 Hom.: 20785 Cov.: 0 AF XY: 0.547 AC XY: 37485 AN XY: 68578

African (AFR) AF: 0.435 AC: 16785 AN: 38596

American (AMR) AF: 0.624 AC: 8909 AN: 14282

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2228 AN: 3396

East Asian (EAS) AF: 0.434 AC: 2121 AN: 4882

South Asian (SAS) AF: 0.653 AC: 2942 AN: 4506

European-Finnish (FIN) AF: 0.591 AC: 4717 AN: 7988

Middle Eastern (MID) AF: 0.772 AC: 213 AN: 276

European-Non Finnish (NFE) AF: 0.567 AC: 37176 AN: 65518

Other (OTH) AF: 0.578 AC: 1124 AN: 1944

Alfa AF: 0.280 Hom.: 575

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Breast neoplasm (1)
-	-	1	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs34325032; hg19: chr11-108121410; COSMIC: COSV53729214;