11-108310222-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

The NM_000051.4(ATM):c.5825C>T(p.Ala1942Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,392 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. A1942S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 7.28

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000051.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 11-108310222-C-T is Pathogenic according to our data. Variant chr11-108310222-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181999.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5825C>T	p.Ala1942Val	missense_variant	39/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5825C>T	p.Ala1942Val	missense_variant	39/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251070 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135718

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461332 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726992

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74268

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2022	Not observed at a 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: 25754356, 24090759, 22649200, 29641532, 34602955, 26896183) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 24, 2023	PM2_supporting, PM3_very_strong -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 26, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26896183, 22649200, 24090759, 34602955]. Functional studies indicate this variant impacts protein function [PMID: 26896183, 22649200, 24090759]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 15, 2022	This missense variant replaces alanine with valine at codon 1942 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported in three individuals affected with classic ataxia telangiectasia in compound heterozygosity with a known pathogenic variant (PMID: 22649200, 34602955). Cells from two of these patients showed significantly reduced levels of ATM protein (5% of wild type) and undetectable ATM kinase activity (PMID: 22649200). This variant has also been reported in compound heterozygosity with a pathogenic splice variant in an individual affected with a mild form of ataxia telangiectasia, who died at age 48 with pancreatic adenocarcinoma (PMID: 24090759). This variant has been identified in 1/251070 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 30, 2024	The p.A1942V variant (also known as c.5825C>T), located in coding exon 38 of the ATM gene, results from a C to T substitution at nucleotide position 5825. The alanine at codon 1942 is replaced by valine, an amino acid with similar properties. This alteration has been detected in conjunction with the ATM mutation, c.7638_7646delTAGAATTTC, in two siblings with ataxia-telangiectasia (A-T) (Carney EF et al. J Immunol. 2012 Jul;189:261-8). Functional assays performed on their cells showed a high level of chromosomal radiosensitivity and absence of ATM kinase activity (Carney EF et al. J Immunol. 2012 Jul;189:261-8). The ATM p.A1942V variant has also been reported in conjunction with the ATM mutation, c.1898+2T>G, in a second individual with A-T (Davis MY et al. J. Neurol. Sci. 2013 Dec;335:134-8). In another study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Ataxia-telangiectasia syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2023	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia telangiectasia (A-T) (PMID: 22649200, 24090759; Invitae). 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: 181999). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 22649200). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1942 of the ATM protein (p.Ala1942Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.42	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.45		Loss of ubiquitination at K1943 (P = 0.1202);Loss of ubiquitination at K1943 (P = 0.1202);
MVP		0.96
MPC		0.58
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.76

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: rs730881394; hg19: chr11-108180949;