rs1312313805

Variant names:

• chr11-108252024-C-A
• NM_000051.4:c.1795C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108252024-C-A
• chr11-108252024-C-G
• chr11-108252024-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.1795C>A​(p.Leu599Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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=0.1149925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.1795C>A	p.Leu599Ile	missense_variant	Exon 11 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1795C>A	p.Leu599Ile	missense_variant	Exon 11 of 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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 04, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting, BP4 c.1795C>A, located in exon 11 of the ATM gene, is predicted to result in the substitution of leucine by isoleucine at codon 599, p.(Leu599Ile). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.069) suggests that it does not affect the protein function (BP4). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. In addition, the variant is not present in the ClinVar nor the LOVD database. Based on currently available information, the variant c.1795C>A should be considered an uncertain significance variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.061	.;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.62	T;T;.
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	.;L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.069
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.060	.;B;B
Vest4		0.23, 0.31
MutPred		0.29		Loss of catalytic residue at L599 (P = 0.0075);Loss of catalytic residue at L599 (P = 0.0075);Loss of catalytic residue at L599 (P = 0.0075);
MVP		0.74
MPC		0.14
ClinPred		0.22	T
GERP RS		4.2
Varity_R		0.064
gMVP		0.087

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-108122751; COSMIC: COSV99586573; COSMIC: COSV99586573;