NM_000051.4:c.2455T>C

Variant names:

• chr11-108259064-T-C
• rs775644968
• NM_000051.4:c.2455T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000051.4(ATM):​c.2455T>C​(p.Cys819Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,500 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C819Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 3.78
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787
• PP5: Variant 11-108259064-T-C is Pathogenic according to our data. Variant chr11-108259064-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226114.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2455T>C	p.Cys819Arg	missense_variant	Exon 16 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2455T>C	p.Cys819Arg	missense_variant	Exon 16 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250840 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460500 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726600

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111398

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2 Uncertain:1

Feb 19, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This inherited recessive likely pathogenic mutation in the ATM gene was observed in combination with a second recessive pathogenic mutation in the ATM gene, NM_000051.2:c.8264_8268del, in a patient with ataxia-telangectasia. -

Nov 02, 2023

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 arginine, which is basic and polar, at codon 819 of the ATM protein (p.Cys819Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 35154108). 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: 226114). 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. 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. -

Mar 17, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.2455T>C (p.Cys819Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.2455T>C has been reported in the literature in at-least one individual affected with Ataxia-Telangiectasia who carries a pathogenic variant in trans (example: Blanchard-Rohner_2022). At least one publication reports experimental evidence evaluating an impact on protein function. Specifically, no detectable protein and consequently, no kinase activity was found in a lymphoblastoid cell line from an individual with Ataxia-Telangiectasia carrying the variant of interest in trans with a pathogenic null ATM variant (example: Blanchard-Rohner_2022). The following publication has been ascertained in the context of this evaluation (PMID: 35154108). ClinVar contains an entry for this variant (Variation ID: 226114). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 07, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C819R variant (also known as c.2455T>C), located in coding exon 15 of the ATM gene, results from a T to C substitution at nucleotide position 2455. The cysteine at codon 819 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been confirmed in trans with a ATM pathogenic variant in an individual diagnosed with ataxia telangiectasia (Blanchard-Rohner G et al. Front Immunol, 2022 Jan;13:791522). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Feb 06, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 35154108) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	T;T;.
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.7	.;M;M
PhyloP100		3.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.96	.;P;P
Vest4		0.92, 0.89
MutPred		0.60		Loss of methylation at K820 (P = 0.0151);Loss of methylation at K820 (P = 0.0151);Loss of methylation at K820 (P = 0.0151);
MVP		0.98
MPC		0.69
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.50
gMVP		0.76
Mutation Taster		=65/35	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775644968; hg19: chr11-108129791;