rs748634900

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000051.4(ATM):c.8293G>A(p.Gly2765Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.49

Variant links:

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 links:

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]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 11-108343246-G-A is Pathogenic according to our data. Variant chr11-108343246-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.8293G>A	p.Gly2765Ser	missense_variant	57/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.8293G>A	p.Gly2765Ser	missense_variant	57/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251386

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135858

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727170

show subpopulations

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 23, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2765 of the ATM protein (p.Gly2765Ser). This variant is present in population databases (rs748634900, gnomAD 0.002%). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 10534763, 19781682, 21792198, 37438524). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 186351). 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 disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 19431188, 21792198). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 02, 2024	Variant summary: ATM c.8293G>A (p.Gly2765Ser) results in a non-conservative amino acid change located in the ATM, catalytic domain (IPR044107) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 251598 control chromosomes (gnomAD). c.8293G>A has been reported in the literature in individuals affected Ataxia Telangectasia (A-T) as well as breast cancer patients, however segregation studies in a breast cancer family showed the variant to be absent in an affected grandmother, while the variant was present in two unaffected siblings (age at testing was not specified). This data indicate a lack of co-segregation of this variant with breast cancer in this family (Izatt_1999), although the effect of a limited penetrance, cannot be ruled out. Furthermore, a sample tested at our laboratory also carries another pathogenic BRCA2 c.5946delT. Among the cohort of patients clinically diagnosed with A-T, this variant was seen in compound heterozygosity with other possibly pathogenic variants. Well controlled functional studies have shown the variant to lead to loss of ATM Kinase activity, while retaining almost complete ATM protein expression (Barone_2009, Reiman_2011). The following publications have been ascertained in the context of this evaluation (PMID: 19431188, 21787400, 19781682, 10534763, 15928302, 21792198). ClinVar contains an entry for this variant (Variation ID: 186351). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Familial cancer of breast

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 01, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21792198, 19431188, 37438524]. Functional studies indicate this variant impacts protein function [PMID: 21792198, 19431188]. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 20, 2022	This missense variant replaces glycine with serine at codon 2765 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant protein has no detectable kinase activity and leads to cell cycle checkpoint defect in cell-based assays (PMID: 19431188). This variant has been reported in the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 21792198, 25040471). This variant has also been reported in individuals affected with breast cancer (PMID: 10534763, 19781682). This variant has been identified in 2/251386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2024	The p.G2765S pathogenic mutation (also known as c.8293G>A), located in coding exon 56 of the ATM gene, results from a G to A substitution at nucleotide position 8293. The glycine at codon 2765 is replaced by serine, an amino acid with similar properties. This residue resides within the PI-3 kinase functional domain of the ATM protein, and this alteration was demonstrated to result in a protein product that lacks ATM kinase activity, is deficient at the G2/M checkpoint, and interferes with the phosphorylation activity of wild-type ATM (Izatt L et al.Genes Chromosomes Cancer. 1999 Dec; 26(4):286-94; Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30). This mutation has been reported in several patients with a clinical diagnosis of ataxia-telangiectasia, including a woman with ataxia-telangiectasia and breast cancer diagnosed under the age of 50 (Reiman A et al. Br. J. Cancer. 2011 Aug; 105(4):586-91; Taylor AM et al. Clin. Genet. 2014 Jul; Ambry Internal Data). This alteration was also observed in 1/4112 breast cancer patients and 0/2399 healthy controls (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct; 85(4):427-46). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2024

Published functional studies demonstrate a damaging effect: no detectable kinase activity and defective G2/M checkpoint (PMID: 19431188); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10534763, 23532176, 37438524, 21787400, 25040471, 15928302, 30612635, 29922827, 21792198, 19781682, 19431188) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

4.5

H;H

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.97

Gain of phosphorylation at G2765 (P = 0.2191);Gain of phosphorylation at G2765 (P = 0.2191);

MVP

0.98

MPC

0.58

ClinPred

1.0

GERP RS

5.6

Varity_R

0.95

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over