rs202160435

Positions:

• chr11-108247072-G-A
• chr11-108247072-G-C
• chr11-108247072-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5 BP4 BP6

The NM_000051.4(ATM):​c.1010G>A​(p.Arg337His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R337C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:5
• Conservation: PhyloP100: 9.26

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108247071-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.34547788).
• BP6: Variant 11-108247072-G-A is Benign according to our data. Variant chr11-108247072-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127328.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=10, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.1010G>A	p.Arg337His	missense_variant	8/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.1010G>A	p.Arg337His	missense_variant	8/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251160 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135764

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000116

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: 0.0000746 AC: 109 AN: 1461586 Hom.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56 AN XY: 727088

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ATM: PM2, PM5, BP1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 21, 2017	The ATM c.1010G>A (p.Arg337His) variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 25186627 (2015), 28779002 (2017), 29522266 (2018), 30303537 (2019)), prostate cancer (PMID: 33436325 (2021)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), and retinoblastoma (PMID: 26580448 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). In a functional study, fibroblasts homozygous for this variant had normal radiation sensitivity (PMID: 30425284 (2018)), however, further studies are required to determine the global effect of this variant on ATM protein function. The frequency of this variant in the general population, 0.00012 (14/113538 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2023	Observed in individuals with breast, prostate and other cancers, and also in unaffected controls (PMID: 25186627, 26580448, 28779002, 28652578, 29522266, 30303537, 33436325); 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: 22484628, 29522266, 25078331, 23103869, 27586204, 22037554, 23788652, 24997986, 27067779, 28480077, 24356096, 28179590, 25186627, 28779002, 30303537, 30814645, 32183301, 33436325, 35047863, 33646313, 25882375, 19781682, 36361687, 26580448, 34921020, 35264596, 33415580, 28652578, 20305132) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 04, 2024	This missense variant replaces arginine with histidine at codon 337 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20305132, 23555315, 25186627, 29522266, 30303537, 33471991) or prostate cancer (PMID: 33436325), but also in control individuals (PMID: 23555315, 30303537, 33471991). This variant has been identified in 20/251160 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	curation	Sema4, Sema4	Jan 14, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 26, 2019	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. -

Familial cancer of breast Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 24, 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	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 17, 2022	The ATM c.1010G>A (p.Arg337His) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast and/or cancer (PMID: 30303537, 33646313) and in individuals with prostate cancer (PMID: 33436325) and pancreatic cancer (PMID: 35047863). This variant is present in three individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Oct 08, 2019	This variant has been reported in the literature in individuals with breast cancer (Tung 2015, Decker 2017, Hauke 2018). This variant has an overall allele frequency of 0.00008 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. PP3 -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2023	Variant summary: ATM c.1010G>A (p.Arg337His) 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 8.5e-05 in 271398 control chromosomes (gnomAD and publications). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. c.1010G>A has been reported in the literature in individuals affected with Breast Cancer and other tumor phenotypes, including prostate cancer and pediatric retinoblastoma (e.g. Bernstein_2010, Zhang_2015, Tung_2015, Decker_2017, Hauke_2018, Girard_2019, Karlsson_2021, Dorling_2021), but was also found in healthy controls (e.g. Tiao_2017, Girard_2019, Dorling_2021, and in three women older than 70 years of age who have never had cancer, in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25882375, 24356096, 20305132, 28779002, 22529920, 30303537, 29522266, 30814645, 28652578, 25186627, 26580448, 33436325, 33471991). Ten other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=7), likely benign (n=2) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Ataxia-telangiectasia syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Apr 09, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 30, 2022

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Arg337His variant was not identified in the literature nor was it identified in the COGR, MutDB, LOVD 3.0, and ATM-LOVD databases or the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs202160435) as “With Uncertain significance allele”, in ClinVar and Clivitae databases with uncertain significance by GeneDx, Ambry Genetics and Invitae); in the Cosmic database 12X in bladder, colon, rectal, gallbladder and stomach carcinomas. The variant was also identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004). The variant was identified in control databases in 19 of 245972 chromosomes at a frequency of 0.000077 in the following populations: African in 1 of 15292chromosomes (freq. 0.00007), Latino in 2 of 33536 chromosomes (freq. 0.00006), European Non-Finnish in 15 of 111508 chromosomes (freq. 0.0001), South Asian in 1 of 30782 chromosomes (freq. 0.00003), but was not seen in Ashkenazi Jewish, East Asian, European Finnish and Other populations, increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg337His residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Armadillo-type fold functional domain. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;.
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	D;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.83, 0.87
MutPred		0.60		Loss of catalytic residue at R337 (P = 0.0331);Loss of catalytic residue at R337 (P = 0.0331);Loss of catalytic residue at R337 (P = 0.0331);
MVP		0.98
MPC		0.64
ClinPred		0.56	D
GERP RS		5.7
Varity_R		0.38
gMVP		0.53

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: rs202160435; hg19: chr11-108117799; COSMIC: COSV53723910; COSMIC: COSV53723910;