11-108304735-G-A

Variant names:

• chr11-108304735-G-A
• rs1801516
• NM_000051.4:c.5557G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.5557G>A​(p.Asp1853Asn) variant causes a missense change. The variant allele was found at a frequency of 0.13 in 1,613,666 control chromosomes in the GnomAD database, including 15,385 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1853V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1205 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14180 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:25 O:1
• Conservation: PhyloP100: 5.93
• Publications: 340 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):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014446676).
• BP6: Variant 11-108304735-G-A is Benign according to our data. Variant chr11-108304735-G-A is described in ClinVar as Benign. ClinVar VariationId is 128458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.5557G>A	p.Asp1853Asn	missense	Exon 37 of 63	NP_000042.3
	ATM	NM_001351834.2		c.5557G>A	p.Asp1853Asn	missense	Exon 38 of 64	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.5557G>A	p.Asp1853Asn	missense	Exon 37 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.5557G>A	p.Asp1853Asn	missense	Exon 38 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*621G>A		non_coding_transcript_exon	Exon 35 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16174 AN: 152020 Hom.: 1205 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.0907

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0749

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.114 AC: 28505 AN: 250874 AF XY: 0.116

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.0612

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.00632

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.133 AC: 193944 AN: 1461528 Hom.: 14180 Cov.: 33 AF XY: 0.132 AC XY: 95950 AN XY: 727062

African (AFR) AF: 0.0206 AC: 690 AN: 33472

American (AMR) AF: 0.0646 AC: 2890 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3491 AN: 26130

East Asian (EAS) AF: 0.00313 AC: 124 AN: 39676

South Asian (SAS) AF: 0.0775 AC: 6683 AN: 86250

European-Finnish (FIN) AF: 0.236 AC: 12577 AN: 53376

Middle Eastern (MID) AF: 0.119 AC: 689 AN: 5768

European-Non Finnish (NFE) AF: 0.143 AC: 159492 AN: 1111756

Other (OTH) AF: 0.121 AC: 7308 AN: 60380

GnomAD4 genome AF: 0.106 AC: 16176 AN: 152138 Hom.: 1205 Cov.: 32 AF XY: 0.108 AC XY: 8064 AN XY: 74354

African (AFR) AF: 0.0240 AC: 996 AN: 41508

American (AMR) AF: 0.0906 AC: 1385 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 497 AN: 3468

East Asian (EAS) AF: 0.00791 AC: 41 AN: 5184

South Asian (SAS) AF: 0.0758 AC: 366 AN: 4828

European-Finnish (FIN) AF: 0.238 AC: 2510 AN: 10546

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9837 AN: 68000

Other (OTH) AF: 0.103 AC: 217 AN: 2110

Alfa AF: 0.128 Hom.: 5648

Bravo AF: 0.0928

TwinsUK AF: 0.140 AC: 518

ALSPAC AF: 0.148 AC: 572

ESP6500AA AF: 0.0284 AC: 125

ESP6500EA AF: 0.140 AC: 1205

ExAC AF: 0.110 AC: 13333

Asia WGS AF: 0.0370 AC: 130 AN: 3476

EpiCase AF: 0.141

EpiControl AF: 0.139

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	-	4	Ataxia-telangiectasia syndrome (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	2	Familial cancer of breast (2)
-	-	1	ATM-related cancer predisposition (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.20	T
Sift4G	Benign	0.13	T
Polyphen		0.044	B
Vest4		0.31
MPC		0.13
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.44
gMVP		0.30
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1801516; hg19: chr11-108175462; COSMIC: COSV53728020; COSMIC: COSV53728020;