11-108343371-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000051.4(ATM):c.8418G>T(p.Met2806Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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, splice_region

Scores

Splicing: ADA: 0.9976

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.82

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 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-108343371-G-T is Pathogenic according to our data. Variant chr11-108343371-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1481088.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 link	c.8418G>T	p.Met2806Ile	missense_variant, splice_region_variant	Exon 57 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.8418G>T	p.Met2806Ile	missense_variant, splice_region_variant	Exon 57 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251020

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135658

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461530

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727062

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00210

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:2

Feb 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2806 of the ATM protein (p.Met2806Ile). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs762744146, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 1481088). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 57, but is expected to preserve the integrity of the reading-frame (Invitae). This variant disrupts a region of the ATM protein in which other variant(s) (p.Gly2765Ser) have been determined to be pathogenic (PMID: 10534763, 19781682, 21792198). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 24, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.8418G>T (p.Met2806Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes the canonical 5' splicing donor site. Three predict the variant weakens the canonical 5' donor site. Internal RNA analysis provides experimental evidence that this variant affects mRNA splicing resulting in the in-frame skipping of exon 57 [NM_000051.3:r.8269_8418del (p.Val2757_Met2806del)]. At-least one additional variant with sufficient pathogenic evidence (c.8293G>A, p.Gly2765Ser) within exon 57 supports a critical relevance of this domain to ATM-protein function. The variant allele was found at a frequency of 4e-06 in 251020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8418G>T in individuals affected with Ataxia-Telangiectasia and/or ATM-related cancers and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1481088). Based on the evidence outlined above, the variant was classified as pathogenic for AR-Ataxia-Telangiectasia and AD-susceptibility to ATM-related cancers. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Nov 13, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8418G>T variant (also known as p.M2806I), located in coding exon 56 of the ATM gene, results from a G to T substitution at nucleotide position 8418. The methionine at codon 2806 is replaced by isoleucine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 56, which makes it likely to have some effect on normal mRNA splicing. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). RNA analysis performed in a woman with invasive breast cancer showed that this alteration causes skipping of coding exon 56 (Shirley BC et al. F1000Res, 2018 Dec;7:1908). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. This nucleotide position is well conserved in available vertebrate species. This amino acid position is not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial cancer of breast

Pathogenic:1

Feb 02, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

0.00031

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

T;.

M_CAP

Benign

0.044

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.20

Sift

Benign

0.27

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.0010

B;B

Vest4

0.34

MutPred

0.43

Loss of disorder (P = 0.0334);Loss of disorder (P = 0.0334);

MVP

0.88

MPC

0.14

ClinPred

0.45

GERP RS

4.9

Varity_R

0.52

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.65

Position offset: 0

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