11-108229243-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000051.4(ATM):c.251C>T(p.Ala84Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A84S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.92

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.127994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.251C>T	p.Ala84Val	missense_variant	4/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.251C>T	p.Ala84Val	missense_variant	4/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250950 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135672

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS 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: 0.00000137 AC: 2 AN: 1461356 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 26, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 84 of the ATM protein (p.Ala84Val). This variant is present in population databases (rs587781937, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 141686). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. 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 cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 18, 2022	The p.A84V variant (also known as c.251C>T), located in coding exon 3 of the ATM gene, results from a C to T substitution at nucleotide position 251. The alanine at codon 84 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Mar 28, 2023	This missense variant replaces alanine with valine at codon 84 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 1/250950 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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 27, 2023

Variant summary: ATM c.251C>T (p.Ala84Val) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 275930 control chromosomes (gnomAD, Momozawa_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.251C>T has been reported in the literature in one individual affected prostate cancer, however co-occurrence with another pathogenic variant has been reported in this individual (BRCA2 c.9070_9073del, p.N3024fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30287823, 31248605). Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2022

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; Observed in at least one unaffected male control and not observed in any female or male breast cancer cases in published literature (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T;T;T;T;T;.;.;.;.;.;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N;N;D;D;.;N;.;.;.;.;.
REVEL	Benign	0.089
Sift	Benign	0.079	T;T;T;T;.;T;.;.;.;.;.
Sift4G	Uncertain	0.028	D;D;D;D;D;D;.;.;.;D;D
Polyphen		0.041, 0.0070	.;B;.;.;.;B;B;B;B;B;.
Vest4		0.22, 0.21, 0.26, 0.13
MutPred		0.14		Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);Loss of disorder (P = 0.0703);
MVP		0.72
MPC		0.16
ClinPred		0.42	T
GERP RS		4.2
Varity_R		0.037
gMVP		0.35

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: rs587781937; hg19: chr11-108099970; COSMIC: COSV53724047; COSMIC: COSV53724047;