rs786203165

Positions:

• chr11-108332024-C-G
• chr11-108332024-C-A
• chr11-108332024-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000051.4(ATM):​c.7775C>G​(p.Ser2592Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,728 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2592P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:9
• Conservation: PhyloP100: 6.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 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, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7775C>G	p.Ser2592Cys	missense_variant	52/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7775C>G	p.Ser2592Cys	missense_variant	52/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250918 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135612

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461556 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727088

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: 0.0000414

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74334

Gnomad4 AFR AF: 0.00

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: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 18, 2024	The p.S2592C variant (also known as c.7775C>G), located in coding exon 51 of the ATM gene, results from a C to G substitution at nucleotide position 7775. The serine at codon 2592 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been identified in an individual diagnosed with ataxia telangiectasia; however a second ATM alteration was not documented (Neubauer S et al. Radiat Res, 2002 Mar;157:312-21). This alteration has been reported in 1/4,112 breast cancer cases and 0/2,399 controls in a meta-analysis of the role of the ATM gene in breast cancer susceptibility (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This variant has also been detected in cohorts of patients with non-Hodgkin lymphoma, multiple primary tumors, and prostate cancer (Sipahimalani P et al. Int. J. Cancer. 2007 Nov;121:1967-75; Abida W et al. JCO Precis Oncol. 2017 Jul;2017; Whitworth J et al. Am. J. Hum. Genet. 2018 Jul;103:3-18; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). In functional studies, this variant demonstrated an absence of kinase activity in vivo and in vitro, and increased sensitivity to ionizing radiation (Scott SP et al. Proc. Natl. Acad. Sci. U.S.A. 2002 Jan;99:925-30). Scott et al. also demonstrated the ability of the p.S2592C variant to interfere with wild-type kinase activity in a dominant negative fashion. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Jan 08, 2024	This missense variant replaces serine with cysteine at codon 2592 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has reported that this variant protein has no detectable kinase activity and fails to rescue the elevated radiosensitivity and chromosome aberration phenotype in ATM-deficient cells (PMID: 11805335). This variant has been observed in individuals affected with breast cancer (PMID: 11606401, 19781682, 26898890, 28779002), prostate cancer (PMID: 28825054), non-Hodgkin lymphoma (PMID: 17640065) and multiple primary tumors (PMID: 29909963) and in an unaffected control in a breast cancer case-control study (PMID: 28779002). In a separate, international case-control meta-analysis, this variant was reported in 4/60466 breast cancer cases and 6/53461 controls (OR=0.589, 95%CI 0.166 to 2.089, p-value=0.531; PMID: 33471991). This variant has been identified in 4/250918 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. -
Likely pathogenic, flagged submission	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2022	Variant summary: ATM c.7775C>G (p.Ser2592Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250918 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7775C>G has been reported in the literature as a heterozygous carrier genotype in individuals with a variety of cancers such as breast, non-Hodgkin lymphoma (NHL), Multiple primary tumors (MPTs), Prostate Cancer and other ATM-associated tumors (example, Dork_2001, Scott_2002, Bremer_2003, Meyer_2004, Sipahimalni_2007, Whitworth_2018, Karlsson_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/ATM-related cancers. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating 1. a lack of ATM-kinase activity in vitro, 2. dominantly interfered with ATM kinase activity in wild type cells by preventing activation of endogenous ATM kinase in vitro and in vivo, 3. failed to correct the radiosensitivity and elevated chromosomal abberations in AT1ABR cells, lastly, 4. cells transfected with S2592C showed enhanced sensitivity to radiation similar to that of an AT cell line (Scott_2002). However, the data as presented in this study were not quantified to a residual activity. This study has been widely cited listing this as a "Kinase Dead" (KD) variant of ATM (example, Putti_2021). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=7; LP, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional consensus opinions around this variant evolve, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 02, 2022	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2592 of the ATM protein (p.Ser2592Cys). This variant is present in population databases (rs755009196, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer, prostate cancer, or Non-Hodgkin's lymphoma (PMID: 11606401, 11805335, 17640065, 19781682, 28825054, 29909963). ClinVar contains an entry for this variant (Variation ID: 186713). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 11805335). 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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2022	Published functional studies suggest a damaging effect: absent kinase activity, increased radiosensitivity in vitro, and dominant interfering effect (Scott et al., 2002); Reported in individuals with breast or prostate cancer, but also in healthy controls (Dork et al., 2001; Tavtigian et al., 2009; Caminsky et al., 2016; Abida et al., 2017; Decker et al., 2017; Karlsson et al., 2021); 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; This variant is associated with the following publications: (PMID: 19781682, 11606401, 15279808, 14643952, 16652348, 21910157, 12552566, 18568480, 16112413, 11839094, 12810666, 12969974, 21787400, 12511424, 20346647, 15450731, 28825054, 28779002, 28873162, 26898890, 29909963, 27535533, 33436325, 11805335) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 28, 2020	- -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.62
MutPred		0.78		Loss of phosphorylation at S2592 (P = 0.0326);Loss of phosphorylation at S2592 (P = 0.0326);
MVP		0.96
MPC		0.54
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.37
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs755009196; hg19: chr11-108202751;