rs121434222

chr11-108287687-C-Gchr11-108287687-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000051.4(ATM):c.4081C>G(p.Gln1361Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. Q1361R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.25

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0845691).
• BP6: Variant 11-108287687-C-G is Benign according to our data. Variant chr11-108287687-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 921313.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4081C>G	p.Gln1361Glu	missense_variant	27/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4081C>G	p.Gln1361Glu	missense_variant	27/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 05, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	12
Dann	Benign	0.16
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.67	T;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.25	N;N;N;.
REVEL	Benign	0.091
Sift	Benign	0.78	T;T;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.17, 0.17
MutPred		0.18		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;
MVP		0.74
MPC		0.13
ClinPred		0.12	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.11

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: rs121434222; hg19: chr11-108158414; COSMIC: COSV53759420;