11-108330257-G-C

Position:

• chr11-108330257-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000051.4(ATM):​c.7351G>C​(p.Ala2451Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.28

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]

ATM (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.7351G>C	p.Ala2451Pro	missense_variant	50/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7351G>C	p.Ala2451Pro	missense_variant	50/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2020

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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127441). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 2451 of the ATM protein (p.Ala2451Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 19, 2014

An ATM variant displaying apparent mosaicism was detected, meaning the variant was detected in some, but not all, cells. This variant is denoted ATM c.7351G>C at the cDNA level, p.Ala2451Pro (A2451P) at the protein level, and results in the change of an Alanine to a Proline (GCC>CCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala2451Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative amino acid substitution, altering a position that is well conserved throughout evolution and is located in the FAT domain (UniProt). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on the currently available information, we consider ATM Ala2451Pro to be a variant of uncertain significance. This variant appears to be mosaic, as the variant allele was present but underrepresented in comparison to the normal allele. This result was confirmed using alternate, non-overlapping primers, making it unlikely that this result is due to uneven DNA amplification. Therefore, this variant is interpreted to be present in some, but not all, cells in this peripheral blood specimen. Neither Sanger nor Next Generation sequencing is a quantitative test; thus, it is not possible to determine more precisely the level of mosaicism in this specimen. Moreover, the level of mosaicism may be different in other tissues. As somatic mosaicism generally results from a post-zygotic event, parents and siblings are not likely at risk to carry this mosaic variant. Germline mosaicism and transmission to the offspring of this patient, however, cannot be excluded. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2019

The p.A2451P variant (also known as c.7351G>C), located in coding exon 49 of the ATM gene, results from a G to C substitution at nucleotide position 7351. The alanine at codon 2451 is replaced by proline, an amino acid with highly similar 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.60
Sift	Benign	0.099	T;T
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;D
Vest4		0.68
MutPred		0.63		Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.98
MPC		0.60
ClinPred		0.86	D
GERP RS		3.8
Varity_R		0.78
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs587779862; hg19: chr11-108200984;