11-108284231-T-C

Position:

• chr11-108284231-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000051.4(ATM):​c.3751T>C​(p.Cys1251Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1251F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.55

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42102787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.3751T>C	p.Cys1251Arg	missense_variant	26/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3751T>C	p.Cys1251Arg	missense_variant	26/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247498 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134254

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: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453584 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723416

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 13, 2023	The p.C1251R variant (also known as c.3751T>C), located in coding exon 25 of the ATM gene, results from a T to C substitution at nucleotide position 3751. The cysteine at codon 1251 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 04, 2019	- -

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2023

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 453491). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is present in population databases (rs763730862, gnomAD 0.003%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1251 of the ATM protein (p.Cys1251Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Uncertain	0.50	.;T;T
Eigen	Benign	0.0043
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T;T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.6	.;M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.43	T;T;T
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.39	.;B;B
Vest4		0.78, 0.76
MutPred		0.72		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.89
MPC		0.24
ClinPred		0.20	T
GERP RS		5.7
Varity_R		0.77
gMVP		0.67

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: rs763730862; hg19: chr11-108154958;