11-108307975-G-C

Variant names:

• chr11-108307975-G-C
• rs148064985
• NM_000051.4:c.5753G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000051.4(ATM):​c.5753G>C​(p.Arg1918Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000453 in 1,610,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1918R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:19 B:3
• Conservation: PhyloP100: 5.87
• Publications: 10 publications found

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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 0 benign, 40 uncertain in NM_000051.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.5753G>C	p.Arg1918Thr	missense_variant	Exon 38 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5753G>C	p.Arg1918Thr	missense_variant	Exon 38 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 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: 0.000478

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250990 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000473 AC: 69 AN: 1458320 Hom.: 0 Cov.: 30 AF XY: 0.0000469 AC XY: 34 AN XY: 725664

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.000112 AC: 5 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.0000541 AC: 60 AN: 1108978

Other (OTH) AF: 0.0000332 AC: 2 AN: 60268

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:19 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6 Benign:1

Nov 01, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BP4 -

Nov 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of breast, pancreatic, or other cancers, as well as in unaffected control groups (PMID: 17640065, 20305132, 28779002, 28652578, 30303537, 32658311, 32255556, 35957908, 35534704, 36717774, 33471991, 33606809, 39015540); This variant is associated with the following publications: (PMID: 17640065, 28779002, 20305132, 25938944, 26662178, 28652578, 30303537, 32255556, 32658311, 31382929, 33471991, 33606809, 35957908, 35534704, 36717774, 39015540) -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Arg1918Thr variant was identified in 3 of 4478 proband chromosomes (frequency: 0.0007) from individuals or families with non-Hodgkin lymphoma, breast cancer, and colonic adenoma (Sipahimalani 2007, Bernstein 2010, Weren 2015). The variant was also identified in dbSNP (ID: rs148064985) as "With Uncertain significance allele", ClinVar (5x uncertain significance) and Clinvitae. The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, or the ATM-LOVD database. The variant was identified in control databases in 16 of 245800 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 5464 chromosomes (freq: 0.0002), Latino in 3 of 33534 chromosomes (freq: 0.00009), and European in 12 of 111494 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg1918 residue is conserved in mammals but not in more distantly related organisms. However four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -

Jun 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:5

Jun 15, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1918T variant (also known as c.5753G>C), located in coding exon 37 of the ATM gene, results from a G to C substitution at nucleotide position 5753. The arginine at codon 1918 is replaced by threonine, an amino acid with similar properties. This variant has been identified in breast cancer cohorts (Bernstein JL et al. J. Natl. Cancer Inst., 2010 Apr;102:475-83; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This amino acid position is well 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. -

Feb 10, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with threonine at codon 1918 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, 28779002, 30303537, 32658311, 33471991, 33606809), melanoma (PMID: 31382929), pancreatic cancer (PMID: 32255556, 36717774), non-Hodgkin lymphoma (PMID: 17640065), and individuals with personal and/or family history of colorectal cancer or polyposis (PMID: 25938944). However it has also been observed in healthy controls (PMID: 33471991). This variant has been identified in 15/250990 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. -

Jan 13, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.5753G>C, located in exon 38 of the ATM gene, is predicted to result in the substitution of Arginine by Threonine at codon 1918, p.(Arg1918Thr).This variant is found in 15/267899 alleles at a frequency of 0.005% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score (0.26) for this variant is indeterminate regarding the effect that it may have on protein function according Pejaver 2022 thresholds (PMID: 36413997). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. It has been reported in ClinVar (16x uncertain significance, 2x likely benign). Based on currently available information, the variant c.5753G>C should be considered an uncertain significance variant. -

Jan 07, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Ataxia-telangiectasia syndrome Uncertain:3 Benign:1

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:2

Oct 16, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2024

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with threonine at codon 1918 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. This variant has been reported in individuals affected with breast cancer (PMID: 20305132, 28779002, 30303537, 32658311, 33471991), melanoma (PMID: 31382929), pancreatic cancer (PMID: 32255556), non-Hodgkin lymphoma (PMID: 17640065), and individuals with personal and/or family history of colorectal cancer or polyposis (PMID: 25938944). However it has also been observed in healthy controls (PMID: 33471991). This variant has been identified in 15/250990 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. Pathogenic/likely pathogenic mutations in the ATM gene cause susceptibility to breast cancer (OMIM 114480). -

not specified Uncertain:1

Sep 21, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.5753G>C (p.Arg1918Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250990 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (6e-05 vs 0.001), allowing no conclusion about variant significance. c.5753G>C has been reported in the literature as a VUS/non-causative variant in settings of multigene panel testing of individuals affected with a variety of cancers such as breast, Non-Hodgkins lymphoma, colorectal and pancreatic adenocarcinoma (example, Bernstein_2010, Sipahimalani_2007, Weren_2015, Cremin_2020, Ackay_2021, Sandoval_2021). 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: 32658311, 20305132, 32255556, 33606809, 17640065, 25938944). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=8) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related disorder Uncertain:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.5753G>C variant is predicted to result in the amino acid substitution p.Arg1918Thr. This variant has been reported in individuals with breast cancer, pancreatic cancer, colonic adenomas, colorectal cancer, melanoma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia (Table 2, Sipahimalani et al. 2007. PubMed ID: 17640065; Table S2, Bernstein et al. 2010. PubMed ID: 20305132; Table 4, Weren et al. 2015. PubMed ID: 25938944; Table S5, Decker et al. 2017. PubMed ID: 28779002; Table S6, Tiao et al. 2017. PubMed ID: 28652578; Table S3, Girard et al. 2019. PubMed ID: 30303537; Table S1, Casula et al. 2019. PubMed ID: 31382929; Table S6, Akcay et al. 2020. PubMed ID: 32658311; Table S3, Cremin et al. 2020. PubMed ID: 32255556). It has also been reported in control individuals from a chronic lymphocytic leukemia cohort study (Table S6, Tiao et al. 2017. PubMed ID: 28652578). This variant is reported in 0.0097% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/142535/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1

-

Dipartimento Di Medicina Di Precisione, Università Degli Studi Della Campania Luigi Vanvitelli

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.5753G>C (p.Arg1918Pro) in ATM, located in exon 39, results in the substitution of a conserved arginine residue. This variant was initially classified as a Variant of Uncertain Significance (VUS). However, in silico prediction tools (e.g., REVEL, CADD, PolyPhen-2) suggest a tolerated or benign effect on protein function. Additionally, the variant is rare in population databases and no strong evidence of pathogenicity has been reported in the literature. According to ACMG/AMP guidelines (BP4, BS1), this variant has been reclassified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.060	T;T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		5.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.27
Sift	Benign	0.34	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.098	B;B
Vest4		0.69
MVP		0.86
MPC		0.26
ClinPred		0.071	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.34
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs148064985; hg19: chr11-108178702;