Variant rs587781353 details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 11-108345889-TG-AA is Pathogenic according to our data. Variant chr11-108345889-TG-AA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.8565_8566delinsAA	p.Ser2855_Val2856delinsArgIle	missense_variant	58/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.8565_8566delinsAA	p.Ser2855_Val2856delinsArgIle	missense_variant	58/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 02, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 19431188, 11857346]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9872980, 10817650]. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2013	The c.8565_8566delTGinsAA variant is located in coding exon 57 of the ATM gene. This variant results from a deletion of two nucleotides (TG) and an insertion of two nucleotide (AA) between nucleotide positions 8565 and 8566. This variant results in an amino acid substitution of a serine to an arginine at codon 2855 (p.S2855R) an amino acid with dissimilar properties and a valine to a isoleucine at codon 2856 (p.V2856I) an amino acid with similar properties. In a large case control study of breast cancer patients, c.8565_8566delTGinsAA was reported in 1/4112 cases and in 0/2399 controls and was predicted to be deleterious by A-GVGD and SIFT in-silico models (Tavtigian SV et al. Am J Hum Genet. 2009 Oct;85(4):427-46). This variant is also reported in conjunction with the c.6015insC frameshift mutation in a patient with Ataxia Telangiectasia (A-T) (Hacia JG et al. Genome Res. 1998 Dec;8(12):1245-58).According to the LOVD database, these two alterations in this individual were in trans.In addition, c.8565_8566delTGinsAA is in the highly conserved PI 3-kinase domain and functional studies show that this variant leads to complete loss of the ATM kinase activity (Barone G et al. Hum Mutat. 2009 Aug;30(8):1222-30). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on nucleotide sequence alignment, c.8565 is moderately conserved, however, in those species with different reference nucleotides, all are C at this position leading to a synonymous change at the amnio acid level. Therefore, the p.2855 position is highly conserved in available vertebrate species. In addition the c.8566 nucleotide position and p.2856 amino acid position are also highly conserved in available vertebrate species. Both p.S2855R and p.V2856I changes are predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively.Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 21, 2023	This missense variant replaces serine and valine at codons 2855 and 2856 in the kinase domain of the ATM protein with arginine and isoleucine, respectively. A functional study has shown that the mutant protein is stably expressed but lacks kinase activity (PMID: 19431188). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 9872980, 10817650, 12673797, 19431188). This variant has also been reported in individuals affected with breast cancer, including one affected individual who showed severe radiosensitivity (PMID:16832357, 19781682, 26681312, 28929041). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Ataxia-telangiectasia syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This variant, c.8565_8566delinsAA, is a complex sequence change that results in the deletion of 2 amino acids (Ser2855_Val2856) and insertion of 2 amino acid(s) in the ATM protein (p.Ser2855_Val2856delinsArgIle). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with breast cancer (PMID: 19781682, 26681312, 28929041). 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: 140897). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATM function (PMID: 11857346, 19431188). For these reasons, this variant has been classified as Pathogenic. -

ATM-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2023

The ATM c.8565_8566delinsAA variant is predicted to result in an in-frame deletion and insertion. This variant was reported in the heterozygous state in individuals with breast cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table S1, Susswein et al. 2016. PubMed ID: 26681312). This variant was also reported in the compound heterozygous state in individuals with ataxia telangiectasia (Hacia et al. 1998. PubMed ID: 9872980; Table S1, Jackson et al. 2016. PubMed ID: 26896183). Functional studies showed that this variant results in no detectable kinase activity (Barone et al. 2009. PubMed ID: 19431188). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140897/). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2023

Published functional studies demonstrate a damaging effect: reduced levels of ATM protein and absent kinase activity (Barone et al., 2009); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 26681312, 10817650, 9872980, 11857346, 28929041, 28152038, 32322110, 26896183, 19431188, 35022142, 15279808, 23532176) -

Malignant tumor of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 21, 2023

Variant summary: ATM c.8565_8566delinsAA (p.Ser2855_Val2856delinsArgIle) results in an in-frame deletion-insertion that is predicted to delete 2 amino acids and to insert two amino acids in Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. The variant was absent in 251104 control chromosomes. c.8565_8566delinsAA has been reported in the literature in multiple individuals affected with Breast Cancer (example, Susswein_2016, Tavtigian_2009, Dosani_2017, Renwick_2006), Testicular/ Prostate and other cancers (example, Ramamurthy_2022). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced ATM expression (about 50% of WT) and abolishment of ATM kinase activity (Barone_2009). Furthermore, this variant has been reported as a compound heterozygous state with at-least two different pathogenic variants in individuals with Ataxia-telangiectasia syndrome (example, Jackson_2016). Additionally, at least one variant at the Ser2855 residue has been reported as likely associated with disease (p.Ser2855Arg), suggesting that Ser2855 codon might be functionally important. These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26896183, 26681312, 19781682, 28929041, 16832357, 35022142, 19431188). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (pathogenic, n=1; likely pathogenic, n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

rs587781353

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