NM_000051.4:c.6995T>C

Variant names:

• chr11-108327664-T-C
• rs4988111
• NM_000051.4:c.6995T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP2_Strong BP4 BA1

This summary comes from the ClinGen Evidence Repository: The ATM c.6995T>C (p.Leu2332Pro) variant has a gnomAD v2.1.1 filtering allele frequency of 2.062% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 61756, 500031). In silico protein predictors (ALIGN GVGD: Class C25; REVEL: 0.193; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.01/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 9.04, variant = 9.04)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157165/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.0060 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (11 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign reviewed by expert panel B:27 O:1
• Conservation: PhyloP100: 3.53
• Publications: 19 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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.6995T>C	p.Leu2332Pro	missense	Exon 48 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6995T>C	p.Leu2332Pro	missense	Exon 49 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-18593A>G		intron	N/A	NP_001317297.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.6995T>C	p.Leu2332Pro	missense	Exon 48 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6995T>C	p.Leu2332Pro	missense	Exon 49 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*2059T>C		non_coding_transcript_exon	Exon 46 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 920 AN: 152158 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00162 AC: 407 AN: 251036 AF XY: 0.00116

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000598 AC: 874 AN: 1461632 Hom.: 11 Cov.: 30 AF XY: 0.000528 AC XY: 384 AN XY: 727120

African (AFR) AF: 0.0211 AC: 705 AN: 33474

American (AMR) AF: 0.00119 AC: 53 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

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

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111880

Other (OTH) AF: 0.00129 AC: 78 AN: 60380

GnomAD4 genome AF: 0.00604 AC: 920 AN: 152276 Hom.: 12 Cov.: 32 AF XY: 0.00551 AC XY: 410 AN XY: 74466

African (AFR) AF: 0.0209 AC: 869 AN: 41544

American (AMR) AF: 0.00222 AC: 34 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00226 Hom.: 7

Bravo AF: 0.00694

ESP6500AA AF: 0.0248 AC: 109

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (8)
-	-	6	not provided (6)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Ataxia-telangiectasia syndrome (3)
-	-	2	Familial cancer of breast (2)
-	-	1	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
-	-	1	ATM-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.19
Sift	Benign	0.29	T
Sift4G	Benign	0.33	T
Polyphen		0.0050	B
Vest4		0.19
MVP		0.84
MPC		0.20
ClinPred		0.010	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.55
Mutation Taster		=81/19	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: rs4988111; hg19: chr11-108198391; COSMIC: COSV104592081;