rs786202826

Variant names:

• chr11-108353805-A-G
• rs786202826
• NM_000051.4:c.8711A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108353805-A-G
• chr11-108353805-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.8711A>G​(p.Glu2904Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 11-108353805-A-G is Pathogenic according to our data. Variant chr11-108353805-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.8711A>G	p.Glu2904Gly	missense_variant	Exon 60 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8711A>G	p.Glu2904Gly	missense_variant	Exon 60 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727218

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Sep 30, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8845835]. Functional studies indicate this variant impacts protein function [PMID: 9733514, 9244351]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 02, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E2904G variant (also known as c.8711A>G), located in coding exon 59 of the ATM gene, results from an A to G substitution at nucleotide position 8711. The glutamic acid at codon 2904 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in the homozygous state in an individual diagnosed with ataxia telangiectasia (Gilad S, Hum. Mol. Genet. 1996 Apr; 5(4):433-9). This alteration has also been reported in 1/7657 individuals diagnosed with breast cancer (Yang Z et al. Breast Cancer Res Treat, 2019 Apr;174:639-647). Introduction of the missense alteration p.E2904G into a cloned ATM ORF resulted in instability of the recombinant protein. The net effect of this mutation on the recombinant protein was similar to that of most A-T mutations, which are null alleles that produce unstable ATM derivatives and leave the cells without any protein product of the ATM gene. Authors proposed that the highly conserved glutamic acid residue at position 2904 may, therefore, be critical for the protein's stability (Ziv Y, Oncogene 1997 Jul; 15(2):159-67). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Apr 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with glycine at codon 2904 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 results in the loss of stable ATM protein expression and kinase function (PMID: 9244351, 9733514). This variant has been reported in the literature in the homozygous state in an individual affected with ataxia-telangiectasia (PMID: 8845835) and in a BRCA1/2-negative individual affected with breast cancer (PMID: 30607632). 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

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2904 of the ATM protein (p.Glu2904Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 8845835, 28724667). ClinVar contains an entry for this variant (Variation ID: 186276). 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: 9244351). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.2	H;H
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.81		Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);
MVP		0.99
MPC		0.63
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786202826; hg19: chr11-108224532;