rs550552791

Positions:

• chr11-108293425-G-A
• chr11-108293425-G-C
• chr11-108293425-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_000051.4(ATM):​c.4724G>A​(p.Arg1575His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,612,438 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. R1575C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:2
• Conservation: PhyloP100: 8.58

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000051.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79
• BP6: Variant 11-108293425-G-A is Benign according to our data. Variant chr11-108293425-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181960.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4724G>A	p.Arg1575His	missense_variant	31/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4724G>A	p.Arg1575His	missense_variant	31/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 152008 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

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: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000598 AC: 15 AN: 250980 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135664

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000938 AC: 137 AN: 1460430 Hom.: 0 Cov.: 30 AF XY: 0.0000853 AC XY: 62 AN XY: 726640

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 152008 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74238

Gnomad4 AFR AF: 0.0000725

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: 0.0000441

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 16, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease. (PMID: 19431188) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2022	Observed in individuals with ATM-related and other cancers, but also in unaffected controls (Austen et al., 2008; Tavtigian et al., 2009; Skowronska et al., 2012; Navrkalova et al., 2013; Zhang et al., 2015; Pearlman et al., 2017; Hauke et al., 2018; Momozawa et al., 2018); Published functional studies demonstrate no damaging effect: kinase activity similar to wild type (Austen et al., 2008; Barone et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18573109, 26580448, 19781682, 23585524, 26787654, 21933854, 26689913, 27720647, 29522266, 19431188, 30287823, 27978560, 33922147, 30613976) -

Ataxia-telangiectasia syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 03, 2023	This missense variant replaces arginine with histidine at codon 1575 of the ATM protein. Computational prediction suggests that this variant may not affect protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not affect kinase activity of ATM protein (PMID: 18573109, 19431188). This variant has been reported in individuals affected with breast cancer, chronic lymphocytic leukemia, and rectal cancer (PMID: 19781682, 23585524, 27978560, 30287823, 36200007), and in unaffected individuals (PMID: 21933854, 30287823, 34262154). This variant has been detected in a breast cancer case-control meta-analysis in 8/60458 breast cancer cases and 6/53455 controls (OR=1.179, 95%CI 0.409 to 3.398, p-value=0.796; PMID: 33471991). This variant has been identified in 16/282324 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 30, 2023	The p.R1575H variant (also known as c.4724G>A), located in coding exon 30 of the ATM gene, results from a G to A substitution at nucleotide position 4724. The arginine at codon 1575 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in individuals diagnosed with breast cancer and control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Rizzolo P et al. Int J Cancer, 2019 07;145:390-400; Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). This alteration has also been identified in individuals diagnosed with CLL, medulloblastoma and early onset colorectal cancer (Skowronska A et al. Haematologica 2012 Jan;97:142-6; Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Pearlman R et al. JAMA Oncol. 2017 Apr;3(4):464-471). Functional analysis of this alteration found normal protein levels and kinase activity compared to wild type (Austen B et al. Br. J. Haematol. 2008 Sep;142(6):925-33; Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). 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. -

Familial cancer of breast Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 20, 2024	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Jun 27, 2019	The c.4724G>A variant has been reported in the literature to co-occur with the ATM c.6820G>A variant in individuals with breast cancer, chronic lymphocytic leukemia (CLL) and multiple myeloma (Austen 2008, Tavtigian 2008, and Navrkalova 2012). The individual with CLL also had a somatic ATM Gln984Glu and a somatic 11q chromosomal deletion. The c.4724G>A variant has a combined allele frequency of 0.00006 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant is in an evolutionarily conserved residue. Thus, it is unknown whether this variant increases cancer risk. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 16, 2023

Variant summary: ATM c.4724G>A (p.Arg1575His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.9e-05 in 255778 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.9e-05 vs 0.001), allowing no conclusion about variant significance. c.4724G>A has been reported in the literature in individuals affected with Breast Cancer (e.g. Tavtigian_2009, Momozawa_2018, Rizzolo_2019, Bhai_2021), and in individuals with a variety of other cancers (e.g. Austen_2008, Navrkalova_2012, Pearlman_2016, Lu_2015), but also in healthy controls (e.g. Momozawa_2018, Dalmasso_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on ATM kinase activity (Austen_2008). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Seven submitters classified the variant as uncertain significance and one classified it as likely benign. The following publications have been ascertained in the context of this evaluation (PMID: 18573109, 34262154, 26689913, 30287823, 23585524, 27978560, 19781682, 26787654, 30613976, 34326862). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.70
MutPred		0.47		Loss of MoRF binding (P = 0.0176);Loss of MoRF binding (P = 0.0176);
MVP		0.94
MPC		0.62
ClinPred		0.78	D
GERP RS		4.4
Varity_R		0.42
gMVP		0.59

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: rs550552791; hg19: chr11-108164152; COSMIC: COSV53746189; COSMIC: COSV53746189;