rs587779830

Variant names:

• chr11-108271273-C-T
• rs587779830
• NM_000051.4:c.2944C>T
• ATM p.Arg982Cys

Your query was ambiguous. Multiple possible variants found:

• chr11-108271273-C-T
• chr11-108271273-C-A
• chr11-108271273-C-G

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingPM2_Supporting

The NM_000051.4(ATM):c.2944C>T (p.Arg982Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000164 (AC=24) in the gnomAD database across 1,461,598 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000109. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R982H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 184953); p.R982L: Uncertain_significance (ClinVar VariationId 1058846, 2 stars); p.R982P: Uncertain_significance (ClinVar VariationId 653025, 1 star); p.R982= (synonymous): Likely_benign (ClinVar VariationId 2064071, 2 stars); p.R982del: Uncertain_significance (ClinVar VariationId 4618098, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Adenomas and Adenocarcinomas; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 6.31
• 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]

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: Natera, Ambry Genetics
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, G2P, Orphanet, Natera, PanelApp Australia, Ambry Genetics, 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

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 4 benign (OR vs. background: 2.8).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000109 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.2944C>T	p.Arg982Cys	missense	Exon 20 of 63	NP_000042.3
	ATM	NM_001351834.2		c.2944C>T	p.Arg982Cys	missense	Exon 21 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.2944C>T	p.Arg982Cys	missense	Exon 20 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.2944C>T	p.Arg982Cys	missense	Exon 21 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.2944C>T	p.Arg982Cys	missense	Exon 20 of 30	ENSP00000434327.3	H0YDU7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00	AC:0	Hom:0	AN:149984	Cov:32
GnomAD2 exomes	AF: 0.0000199	AC:5	Hom:	AN:251040	Cov:
GnomAD4 exome	AF: 0.0000164	AC:24	Hom:0	AN:1461598	Cov:36
GnomAD4 genome Warning	AF: 0.00	AC:0	Hom:0	AN:149984	Cov:32
TOPMed (Bravo) Warning	AF: 0.0000227	AC:6	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000704	2	28420	0.00	0	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000299	2	66886
SCHEMA(Schizophrenia)	0.0000358	4	111880	0.0000163	3	184112

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Ataxia-telangiectasia syndrome (4)
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	2	-	Familial cancer of breast (2)
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.14
GPN-Star LLR	N/A	-7.3
GPN-Star score	N/A	7.3
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.028	T
Mutation Taster	N/A	44/56	disease causing
MutationAssessor	Uncertain	2.7	M
PhyloP100	Uncertain	6.3
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.58
VESM-3B	Benign	-6.5

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_AG_spliceai	Uncertain	0.30	Position offset: 49
Pangolin (max)	Benign	0.13
Pangolin loss	Benign	0.13	Position offset: -22
SpliceAI score (max)	Uncertain	0.30	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

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: rs587779830;

hg19: chr11-108142000;

COSMIC: COSV53741732;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar