rs775644968

Positions:

• chr11-108259064-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 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:2 U:1
• Conservation: PhyloP100: 3.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id is 226114.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2455T>C	p.Cys819Arg	missense_variant	16/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2455T>C	p.Cys819Arg	missense_variant	16/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

Gnomad4 AFR exome AF: 0.0000299

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

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 02, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Feb 19, 2016	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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2023

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. -

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs775644968; hg19: chr11-108129791;