rs1060501524

Positions:

• chr11-108293365-T-A
• chr11-108293365-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000051.4(ATM):​c.4664T>A​(p.Leu1555His) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,444,366 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 5.43

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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.4664T>A	p.Leu1555His	missense_variant	31/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4664T>A	p.Leu1555His	missense_variant	31/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000173 AC: 25 AN: 1444366 Hom.: 0 Cov.: 29 AF XY: 0.0000167 AC XY: 12 AN XY: 719520

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: 0.0000228

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 1555 of the ATM protein (p.Leu1555His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 17393301, 19781682). ClinVar contains an entry for this variant (Variation ID: 407448). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 16, 2023	The p.L1555H variant (also known as c.4664T>A), located in coding exon 30 of the ATM gene, results from a T to A substitution at nucleotide position 4664. The leucine at codon 1555 is replaced by histidine, an amino acid with similar properties. This alteration has been detected in multiple breast cancer patients (Broeks A et al. Breast Cancer Res. Treat., 2008 Jan;107:243-8; Tavtigian SV et al. Am J Hum Genet, 2009 Oct;85:427-46; Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is highly 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 26, 2021

This sequence change has been previously described in a patient with breast cancer but no other details were provided (PMID: 19781682). This sequence change has not been described in the population databases such as gnomAD and ExAC (dbSNP rs1060501524). The p.Leu1555His change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Leu1555His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, MutationTaster). Due to the lack of functional studies, the clinical significance of the p.Leu1555His change remains unknown at this time. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 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; Identified in patients with breast cancer (Broeks et al., 2008; Tavtigian et al., 2009); This variant is associated with the following publications: (PMID: 19781682, 17393301) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T;.
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.54		Loss of stability (P = 0.0199);Loss of stability (P = 0.0199);
MVP		0.99
MPC		0.66
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.53
gMVP		0.77

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: rs1060501524; hg19: chr11-108164092; COSMIC: COSV53762688; COSMIC: COSV53762688;