NM_000051.4:c.1744T>C

Variant names:

• chr11-108251973-T-C
• rs2235006
• NM_000051.4:c.1744T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):​c.1744T>C​(p.Phe582Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000805 in 1,613,800 control chromosomes in the GnomAD database, including 11 homozygotes. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F582C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (10 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:32 O:1
• Conservation: PhyloP100: 0.131
• Publications: 35 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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050537884).
• BP6: Variant 11-108251973-T-C is Benign according to our data. Variant chr11-108251973-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127342.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000805 (1176/1461450) while in subpopulation MID AF = 0.0229 (131/5714). AF 95% confidence interval is 0.0197. There are 10 homozygotes in GnomAdExome4. There are 681 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

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.1744T>C	p.Phe582Leu	missense	Exon 11 of 63	NP_000042.3
	ATM	NM_001351834.2		c.1744T>C	p.Phe582Leu	missense	Exon 12 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.1744T>C	p.Phe582Leu	missense	Exon 11 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.1744T>C	p.Phe582Leu	missense	Exon 12 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.1744T>C	p.Phe582Leu	missense	Exon 11 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152232 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.000980 AC: 246 AN: 251018 AF XY: 0.00115

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000805 AC: 1176 AN: 1461450 Hom.: 10 Cov.: 31 AF XY: 0.000937 AC XY: 681 AN XY: 727034

African (AFR) AF: 0.000837 AC: 28 AN: 33450

American (AMR) AF: 0.00159 AC: 71 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00192 AC: 166 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.0229 AC: 131 AN: 5714

European-Non Finnish (NFE) AF: 0.000594 AC: 660 AN: 1111776

Other (OTH) AF: 0.00169 AC: 102 AN: 60374

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152350 Hom.: 1 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74508

African (AFR) AF: 0.000216 AC: 9 AN: 41580

American (AMR) AF: 0.00183 AC: 28 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68028

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00107 Hom.: 2

Bravo AF: 0.000858

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000980 AC: 119

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	1	6	Ataxia-telangiectasia syndrome (7)
-	-	7	not specified (8)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	2	Familial cancer of breast (2)
-	-	2	Malignant tumor of breast (2)
-	-	1	Breast and/or ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.9
DANN	Benign	0.56
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.13
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.74		Loss of ubiquitination at K578 (P = 0.1151)
MVP		0.82
MPC		0.14
ClinPred		0.00067	T
GERP RS		1.1
Varity_R		0.086
gMVP		0.15
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2235006; hg19: chr11-108122700; COSMIC: COSV104591948;