11-108297379-C-T

Variant names:

• chr11-108297379-C-T
• rs747317946
• NM_000051.4:c.5002C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_000051.4(ATM):​c.5002C>T​(p.Leu1668Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,460,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1668L) has been classified as Likely benign. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.894
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 11-108297379-C-T is Benign according to our data. Variant chr11-108297379-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220386.
• BP7: Synonymous conserved (PhyloP=0.894 with no splicing effect.

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.5002C>T	p.Leu1668Leu	synonymous	Exon 33 of 63	NP_000042.3
	ATM	NM_001351834.2		c.5002C>T	p.Leu1668Leu	synonymous	Exon 34 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.5002C>T	p.Leu1668Leu	synonymous	Exon 33 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.5002C>T	p.Leu1668Leu	synonymous	Exon 34 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*66C>T		non_coding_transcript_exon	Exon 31 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250644 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1460184 Hom.: 0 Cov.: 29 AF XY: 0.0000234 AC XY: 17 AN XY: 726498

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110570

Other (OTH) AF: 0.0000331 AC: 2 AN: 60346

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000661 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	1	Ataxia-telangiectasia syndrome (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
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.4
DANN	Benign	0.72
PhyloP100		0.89
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs747317946; hg19: chr11-108168106;