11-108253989-C-T

Variant names:

• chr11-108253989-C-T
• rs765965513
• NM_000051.4:c.2074C>T
• ATM p.Arg692Cys

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000051.4(ATM):​c.2074C>T​(p.Arg692Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R692G) has been classified as Likely benign. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:4
• Conservation: PhyloP100: 2.10
• Publications: 6 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Laboratory for Molecular Medicine, Genomics England PanelApp, Ambry Genetics
• 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10034457).
• BP6: Variant 11-108253989-C-T is Benign according to our data. Variant chr11-108253989-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 184752.

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.2074C>T	p.Arg692Cys	missense	Exon 13 of 63	NP_000042.3
	ATM	NM_001351834.2		c.2074C>T	p.Arg692Cys	missense	Exon 14 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.2074C>T	p.Arg692Cys	missense	Exon 13 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.2074C>T	p.Arg692Cys	missense	Exon 14 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.2074C>T	p.Arg692Cys	missense	Exon 13 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251328 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727154

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111944

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74272

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.1
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.10
Sift	Benign	0.14	T
Sift4G	Benign	0.13	T
Varity_R		0.11
gMVP		0.14
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs765965513;

hg19: chr11-108124716;

COSMIC: COSV99591859;