11-108254034-T-C

Variant names:

• chr11-108254034-T-C
• rs4986761
• NM_000051.4:c.2119T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):​c.2119T>C​(p.Ser707Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,392 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S707F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0076 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:30 O:1
• Conservation: PhyloP100: -0.160
• Publications: 87 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=0.0057876706).
• BP6: Variant 11-108254034-T-C is Benign according to our data. Variant chr11-108254034-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00763 (1162/152252) while in subpopulation NFE AF = 0.0119 (809/67998). AF 95% confidence interval is 0.0112. There are 6 homozygotes in GnomAd4. There are 560 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.2119T>C	p.Ser707Pro	missense	Exon 13 of 63	NP_000042.3
	ATM	NM_001351834.2		c.2119T>C	p.Ser707Pro	missense	Exon 14 of 64	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.2119T>C	p.Ser707Pro	missense	Exon 13 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.2119T>C	p.Ser707Pro	missense	Exon 14 of 64	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.2119T>C	p.Ser707Pro	missense	Exon 13 of 30	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1163 AN: 152134 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00878

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00796 AC: 1991 AN: 250180 AF XY: 0.00820

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.00806

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00491

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0110 AC: 16108 AN: 1461140 Hom.: 124 Cov.: 30 AF XY: 0.0109 AC XY: 7903 AN XY: 726884

African (AFR) AF: 0.00155 AC: 52 AN: 33472

American (AMR) AF: 0.00651 AC: 291 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00838 AC: 219 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39656

South Asian (SAS) AF: 0.00474 AC: 409 AN: 86238

European-Finnish (FIN) AF: 0.00569 AC: 302 AN: 53064

Middle Eastern (MID) AF: 0.00989 AC: 57 AN: 5766

European-Non Finnish (NFE) AF: 0.0128 AC: 14264 AN: 1111720

Other (OTH) AF: 0.00848 AC: 512 AN: 60378

GnomAD4 genome AF: 0.00763 AC: 1162 AN: 152252 Hom.: 6 Cov.: 32 AF XY: 0.00752 AC XY: 560 AN XY: 74448

African (AFR) AF: 0.00221 AC: 92 AN: 41556

American (AMR) AF: 0.00877 AC: 134 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00837 AC: 29 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 809 AN: 67998

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0111 Hom.: 30

Bravo AF: 0.00796

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.00781 AC: 948

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0123

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (11)
-	-	7	not provided (7)
-	-	6	Ataxia-telangiectasia syndrome (6)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	2	Familial cancer of breast (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.16
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.25
Sift	Benign	0.37	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.096
MVP		0.74
MPC		0.16
ClinPred		0.0022	T
GERP RS		3.8
Varity_R		0.31
gMVP		0.14
Mutation Taster		=97/3	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: rs4986761; hg19: chr11-108124761; COSMIC: COSV53743430;