rs774281788

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_000051.4(ATM):c.7463G>A(p.Cys2488Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,854 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:8O:2

Conservation

PhyloP100: 5.48

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 Uncertain_significance. Variant got 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 11-108330369-G-A is Pathogenic according to our data. Variant chr11-108330369-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187037.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=2, Uncertain_significance=8, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.7463G>A	p.Cys2488Tyr	missense_variant	50/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.7463G>A	p.Cys2488Tyr	missense_variant	50/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251290

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135802

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:

0.00000410

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727226

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:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:8Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 28, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2024	Observed in individuals with a personal history of chronic lymphocytic leukemia, pancreatic, breast and/or ovarian cancer (PMID: 12810666, 19781682, 23585524, 29522266, 29922827); Published functional studies are inconclusive: no effect on protein levels but results in impaired protein function (PMID: 23585524); 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: 26681312, 27479817, 12810666, 19781682, 25480502, 29922827, 30128536, 26822949, 26247737, 22071889, 36029002, 32183364, 29522266, 31054420, 23532176, 23585524) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 01, 2022	This missense variant replaces cysteine with tyrosine at codon 2488 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). Experimental studies have indicated this protein variant may have an impact on ATM function (PMID: 23585524, 22071889, 36029002). This protein variant has been reported in individuals affected with breast cancer (PMID: 12810666, 19781682, 26822949, 33471991) and chronic lymphocytic leukemia (CLL; PMID: 23585524, 25480502, 26247737, 36029002) in the literature. This variant has been identified in 2/251290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 07, 2024	The p.C2488Y variant (also known as c.7463G>A), located in coding exon 49 of the ATM gene, results from a G to A substitution at nucleotide position 7463. The cysteine at codon is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature in the germline of a CLL patient; functional assessment of this alteration revealed a normal level of ATM protein, but the protein was reported as defective (Navrkalova V et al, Haematologica 2013 Jul; 98(7):1124-31). This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). A different nucleotide change resulting in the same amino acid change, p.C2488Y (c.7463G>T), has also been reported in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46). This amino acid position is highly conserved through mammals, but poorly conserved in reptiles and fish. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 02, 2023

Variant summary: ATM c.7463G>A (p.Cys2488Tyr) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) 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 8e-06 in 251500 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7463G>A has been reported in the literature, primarily in settings of multigene panel testing, in individuals affected with CLL wherein some cases likely have been reported in multiple publications (e.g. Navrkalova_2013, Sutton_2015, te Raa_2015, Spunarova_2019, Tausch_2020, Petrackova_2022, Lampson_2023), in individuals with breast and/or ovarian cancer (e.g. Lhota_2016, Lu_2018), in at least one individual with prostate cancer (e.g. Brady_2022) and in individuals with various other cancer types (e.g. Susswein_2015, Hu_2018, Zhang_2023), all without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with breast or prostate cancer. At least two publications report experimental evidence evaluating an impact on protein function(e.g. Navrkalova_2013, te Raa_2015), however, none of these studies allows convincing conclusions about the variant effect. The variant was reported to not affect protein expression, but diminish autophosphorylation function, though primary evidence was not provided for independent evaluation. The following publications have been ascertained in the context of this evaluation (PMID: 35467778, 29922827, 36315919, 26822949, 30128536, 23585524, 36029002, 32183364, 31054420, 26681312, 25480502, 31919090, 19781682, 12810666, 36627197, 26247737). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance and two classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Ataxia-telangiectasia syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2488 of the ATM protein (p.Cys2488Tyr). This variant is present in population databases (rs774281788, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, and chronic lymphocytic leukemia (PMID: 23585524, 26681312, 29922827, 30128536). ClinVar contains an entry for this variant (Variation ID: 187037). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 23585524). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Apr 09, 2024

According to the ClinGen ACMG ATM v1.1.0 criteria we chose this criterion: PP3 (supporting pathogenic): REVEL 0.883 -

Ataxia-telangiectasia syndrome;C1333600:Hereditary cancer

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Ataxia-telangiectasia syndrome;C0006142:Malignant tumor of breast

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Likely pathogenic and reported on 03-04-2017 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;.

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.026

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.69

Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);

MVP

0.97

MPC

0.70

ClinPred

0.98

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.74

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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