ATM p.Ser111Arg

Variant names:

• chr11-108229323-A-C
• rs2135038774
• ENST00000526567.5:c.331A>C
• ATM p.Ser111Arg

Your query was ambiguous. Multiple possible variants found:

• chr11-108229323-A-C
• chr11-108229325-T-A
• chr11-108229325-T-G
• chr11-108229323-AGT-CGC
• chr11-108229323-AGT-CGA
• chr11-108229323-AGT-CGG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS1_Very_Strong PM2 PM5 BP4

The NM_001351835.2(ATM):​c.331A>C​(p.Ser111Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S111I) has been classified as Likely pathogenic. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_001351835.2 missense
• Scores: Splicing: ADA: 0.1574
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.95
• Publications: 0 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, Laboratory for Molecular Medicine, Genomics England PanelApp, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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

Y_RNA (HGNC:):

ACMG classification

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_001351835.2 (ATM) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108229324-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3349804.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3122018).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351835.2. 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.331A>C	p.Arg111Arg	splice_region synonymous	Exon 4 of 63	NP_000042.3
	ATM	NM_001351835.2		c.331A>C	p.Ser111Arg	missense	Exon 4 of 4	NP_001338764.1	Q6P7P1
	ATM	NM_001351836.2		c.331A>C	p.Ser111Arg	missense	Exon 4 of 4	NP_001338765.1	Q6P7P1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000526567.5	TSL:1	c.331A>C	p.Ser111Arg	missense	Exon 4 of 4	ENSP00000480205.1	Q6P7P1
	ATM	ENST00000675843.1	MANE Select	c.331A>C	p.Arg111Arg	splice_region synonymous	Exon 4 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.331A>C	p.Arg111Arg	splice_region synonymous	Exon 5 of 64	ENSP00000388058.2	Q13315

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460472 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726502

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111174

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.23	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.58	T
PhyloP100		4.0
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.11
Sift	Benign	0.038	D
Sift4G	Uncertain	0.044	D
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.63
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2135038774; hg19: chr11-108100050;