11-108330369-G-A

Variant names:

• chr11-108330369-G-A
• rs774281788
• NM_000051.4:c.7463G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_Strong PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:10 O:2
• Conservation: PhyloP100: 5.48

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 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, Uncertain_significance=9, Pathogenic=1, not_provided=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.7463G>A	p.Cys2488Tyr	missense_variant	Exon 50 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7463G>A	p.Cys2488Tyr	missense_variant	Exon 50 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251290 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135802

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: 6 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

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.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:10 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Pathogenic:1 Uncertain:2

Oct 06, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Uncertain:1

May 20, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2

May 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 04, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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, 38673061), chronic lymphocytic leukemia (CLL; PMID: 23585524, 25480502, 26247737, 36029002, 36315919), and gastric cancer (PMID: 36627197). 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. -

not specified Uncertain:1

Nov 02, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. 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. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1

Feb 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial colorectal cancer type X Uncertain:1

Sep 07, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Apr 09, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

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

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.026	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.67	T
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	D
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

Other links and lift over

dbSNP: rs774281788; hg19: chr11-108201096; COSMIC: COSV53742989; COSMIC: COSV53742989;