11-108329112-C-T

Variant names:

• chr11-108329112-C-T
• rs587779861
• NM_000051.4:c.7181C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_000051.4(ATM):​c.7181C>T​(p.Ser2394Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002064367: "In vitro expression studies have shown that the resulting p.Ser2394Leu protein has absent ATM kinase activity (Barone et al., 2009 and Austen et al., 2008)."" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2394S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 B:1
• Conservation: PhyloP100: 7.90
• Publications: 12 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002064367: "In vitro expression studies have shown that the resulting p.Ser2394Leu protein has absent ATM kinase activity (Barone et al., 2009 and Austen et al., 2008)."; SCV000581469: In vitro analysis indicate this variant has absent ATM kinase activity (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30; Austen B et al. Br. J. Haematol. 2008 Sep; 142(6):925-33).; SCV002053077: Functional studies have shown that this variant protein displays no detectable kinase activity in response to ionizing radiation (PMID: 18573109, 19431188).; SCV000622719: Experimental studies have shown that this missense change affects ATM function (PMID: 18573109, 19431188, 26677768).; SCV005039227: The most pronounced variant effect results in complete loss of ATM-kinase activity (Austen_2008).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 11-108329112-C-T is Pathogenic according to our data. Variant chr11-108329112-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 127437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.7181C>T	p.Ser2394Leu	missense	Exon 49 of 63	NP_000042.3
	ATM	NM_001351834.2		c.7181C>T	p.Ser2394Leu	missense	Exon 50 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-20041G>A		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.7181C>T	p.Ser2394Leu	missense	Exon 49 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.7181C>T	p.Ser2394Leu	missense	Exon 50 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*2245C>T		non_coding_transcript_exon	Exon 47 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Ataxia-telangiectasia syndrome (3)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	not provided (2)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
1	-	-	Familial cancer of breast (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.75		Loss of disorder (P = 0.0262)
MVP		0.97
MPC		0.53
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.80
gMVP		0.70
Mutation Taster		=42/58	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs587779861; hg19: chr11-108199839; COSMIC: COSV53735356; COSMIC: COSV53735356;