rs1060501571

Positions:

• chr11-108301706-G-A
• chr11-108301706-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_Supporting PM3_Supporting PM5_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The c.5236G>A (p.Gly1746Arg) variant in ATM has been demonstrated to cause aberrant splicing, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (Ambry internal data). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant was observed in an individual with Ataxia-Telangiectasia (PMID:26896183), and is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1(RNA), PM2_Supporting, PM3_Supporting, PM5_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16613442/MONDO:0016419/020

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 8.19

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.5236G>A	p.Gly1746Arg	missense_variant	35/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5236G>A	p.Gly1746Arg	missense_variant	35/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461476 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.5236G>A variant (also known as p.G1746R), located in coding exon 34 of the ATM gene, results from a G to A substitution at nucleotide position 5236. The glycine at codon 1746 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in 1 individual from the UK diagnosed with ataxia-telangiectasia (Jackson TJ et al. Dev Med Child Neurol, 2016 07;58:690-7). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor and native splice donor sites. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Jan 25, 2024

The c.5236G>A (p.Gly1746Arg) variant in ATM has been demonstrated to cause aberrant splicing, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (Ambry internal data). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant was observed in an individual with Ataxia-Telangiectasia (PMID:26896183), and is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1(RNA), PM2_Supporting, PM3_Supporting, PM5_Supporting). -

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2022

ClinVar contains an entry for this variant (Variation ID: 407510). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 26896183). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1746 of the ATM protein (p.Gly1746Arg). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.55		Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP		0.97
MPC		0.20
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501571; hg19: chr11-108172433;