rs587781511

chr11-108247029-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_000051.4(ATM):c.967A>G(p.Ile323Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I323M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.75

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 10 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108247029-A-G is Pathogenic according to our data. Variant chr11-108247029-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108247029-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.967A>G	p.Ile323Val	missense_variant	8/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.967A>G	p.Ile323Val	missense_variant	8/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251086 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461144 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726916

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 20, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 323 of the ATM protein (p.Ile323Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 101 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs587781511, gnomAD 0.003%). This missense change has been observed in individuals with ataxia telangiectasia (PMID: 10817650, 23652012, 27664052, 31050087). ClinVar contains an entry for this variant (Variation ID: 141123). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 8 (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 07, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 03, 2023	This c.967A>G variant is predicted to replace isoleucine with valine at codon 323 of the ATM protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing by creating a new splice donor site. An RNA study using cells from a homozygous individual has shown that this variant results in two transcripts: the major one with an out-of-frame deletion including 99 bases of exon 8 and the entire exon 9 (r.967_1235del, p.Ile323Alafs*17) and the minor transcript with only in-frame deletion of 99 bases of exon 8 (r.967_1065del, p.Ile323_Gln355del) (PMID: 31050087). The transcript with the r.967A>G (p.Ile323Val) missense variant was not detected in this study, indicating almost complete splicing defect due to the c.967A>G variant. This variant has been reported in multiple individuals affected with ataxia telangiectasia in compound heterozygous state with another pathogenic variant (PMID: 10817650, 23652012, 27664052) or in homozygous state (PMID: 31050087). This variant has been identified in 2/251086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 17, 2023	The c.967A>G variant (also known as p.I323V), located in coding exon 7 of the ATM gene, results from an A to G substitution at nucleotide position 967. The isoleucine at codon 323 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in individuals diagnosed with ataxia-telangiectasia (AT) (Li M et al. Am J Med Genet. 2000; 92:170-7; Lee P. et al. Nat Commun. 2013;4:1824; Carranza D. et al. Neuromolecular Med. 2017 Mar;19(1):161-174; Berland et al J Allergy Clin Immunol 2019 01;143(1):325-334.e2). This variant was also detected in one individual diagnosed with ovarian cancer (Sugino et al Sci Rep 2019 11;9(1):17808) and one individual diagnosed with pancreatic cancer (Cremin et al Cancer Med 2020 06;9(11):4004-4013). Functional analyses of cells generated from individuals diagnosed with AT with this alteration have shown loss of ATM protein and defects in DNA repair or survival following ionizing radiation (Lee P. et al. Nat Commun. 2013;4:1824; Carranza D. et al. Neuromolecular Med. 2017 Mar;19(1):161-174). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 06, 2022

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2023

Patient-derived cells from a homozygous A-T patient, also harboring another homozygous ATM variant, demonstrated aberrant splicing, resulting an out-of-frame transcript leading to protein truncation (Fievet et al., 2019); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23652012, 22529920, 26659599, 24145436, 10817650, 26246501, 31050087, 29906526, 27664052, 35245693, 31780705, 32255556) -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 11, 2024

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10817650, 27664052]. Functional studies indicate this variant impacts protein function [PMID: 27664052]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T;T;.
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.46	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.98	.;D;D
Vest4		0.17, 0.15
MutPred		0.70		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.92
MPC		0.14
ClinPred		0.50	T
GERP RS		5.7
Varity_R		0.20
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.96		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781511; hg19: chr11-108117756; COSMIC: COSV53761273; COSMIC: COSV53761273;