chr11-108301655-G-C

Variant names:

• chr11-108301655-G-C
• rs3092907
• NM_000051.4:c.5185G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_000051.4(ATM):​c.5185G>C​(p.Val1729Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,613,474 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. V1729A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:19 B:6
• Conservation: PhyloP100: 2.78
• Publications: 15 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 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 37 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.31675065).
• BP6: Variant 11-108301655-G-C is Benign according to our data. Variant chr11-108301655-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127401.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.5185G>C	p.Val1729Leu	missense	Exon 35 of 63	NP_000042.3
	ATM	NM_001351834.2		c.5185G>C	p.Val1729Leu	missense	Exon 36 of 64	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.5185G>C	p.Val1729Leu	missense	Exon 35 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.5185G>C	p.Val1729Leu	missense	Exon 36 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*249G>C		non_coding_transcript_exon	Exon 33 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000995 AC: 25 AN: 251144 AF XY: 0.0000958

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461358 Hom.: 0 Cov.: 31 AF XY: 0.0000949 AC XY: 69 AN XY: 726986

African (AFR) AF: 0.000389 AC: 13 AN: 33458

American (AMR) AF: 0.000380 AC: 17 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5760

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111686

Other (OTH) AF: 0.000364 AC: 22 AN: 60364

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74308

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.000721 AC: 11 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000268

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:19 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:8

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 29, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with ataxia-telangiectasia, including one individual who also carried a homozygous pathogenic ATM variant and another who carried a heterozygous ATM pathogenic variant on the opposite allele (in trans) (PMID: 17124347, 29482223, 33779842); In silico analysis suggests that this missense variant does not alter protein structure/function; Observed in individuals with breast, colorectal, uterine, pancreatic, and prostate cancer (PMID: 28640387, 29522266, 29684080, 30303537, 33471991, 33436325, 35264596, 35534704, 38895864); This variant is associated with the following publications: (PMID: 11443540, 17124347, 22529920, 28640387, 29482223, 28652578, 29684080, 29522266, 19781682, 26689913, 30303537, 33203166, 33436325, 32522261, 35980532, 35264596, 37450374, 34482403, 33779842, 37745463, 37529773, 35534704, 39256447, 33471991, 38895864)

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

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.Val1729Leu variant was identified in 3 of 9436 proband chromosomes (frequency: 0.0003) from individuals or families with cerebellar ataxia, Ataxia telangiectasia, and colorectal cancer, and was present in 2 of 4676 control chromosomes (frequency: 0.0004) from healthy individuals (Coutelier 2018, Magliozzi 2006, Ricker 2017, Tavtigian 2009, Thorstenson 2001). The variant was also identified in the following databases: dbSNP (ID: rs3092907) as "With Uncertain significance allele", ClinVar (1x likely benign, 3x uncertain significance), and Clinvitae. The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in control databases in 28 of 276848 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 6 of 6458 chromosomes (freq: 0.0009), Latino in 6 of 34416 chromosomes (freq: 0.0002), and European in 16 of 126392 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Multiple studies list this variant as a polymorphism and one study found this variant co-occurring with the ATM homozygous pathogenic variant c.9022C>T (p.R3008C) (Magliozzi 2006, Thorstenson 2001, Coutelier 2018), increasing the likelihood this variant may not have clinical significance. The p.Val1729 residue is not conserved in mammals 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 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.

Jan 20, 2020

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:4 Benign:3

Mar 10, 2022

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 08, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Sep 28, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 04, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 23, 2018

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 26, 2024

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2+BP4

Sep 04, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_Moderate c.5185G>C, located in exon 35 of the ATM gene, is predicted to result in the substitution of valine by leucine at codon 1729, p.(Val1729Leu). This variant is found in 27/267992 alleles at a frequency of 0.01% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.405) is ambiguous regarding protein function. To our knowledge, no well-stablished functional studies have been reported for this variant. It has been reported in 3 A-T patients with confident diagnosis, in two of them it was confirmed in trans (PMID: 33779842, 17124347) (PP1_Moderate). It has also been reported in cancer-affected patients (28640387, 28652578, 33203166). This variant has been reported in the ClinVar database (6x likely benign, 14x uncertain significance) and in the LOVD database (1x likely benign, 4x uncertain significance). Based on currently available information, the variant c.5185G>C should be considered an uncertain significance variant.

not specified Uncertain:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 14, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5185G>C, in exon 35 that results in an amino acid change, p.Val1729Leu. This sequence change has been described in the gnomAD database with a frequency of 0.017% in the Latino subpopulation (dbSNP rs3092907). The p.Val1729Leu change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val1729Leu substitution. This sequence change has been reported in one individual with breast cancer (PMID: 30303537). It has also been detected in the homozygous state in one individual with a metabolic presentation ataxia (PMID: 29482223) and in trans with a pathogenic variant in a family with ataxia telangiectasia (PMID: 33779842). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val1729Leu change remains unknown at this time.

Mar 03, 2025

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.5185G>C (p.Val1729Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251330 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0001 vs 0.004), allowing no conclusion about variant significance. c.5185G>C has been reported in the literature as a "polymorphism" in a study of individuals affected with Ataxia-Telangiectasia, as a VUS in settings of multigene panel testing in individuals with a personal and/or family history of breast cancer or pancreatic cancer, and in unaffected controls (example, Magliozzi_2006, Tavtigian_2009, Pereira_2022, Rodrigues_2024). In one family the variant is reported to segregate with disease (example: Shalash_2021). However, these reports do not provide unequivocal conclusions about a penetrant association of the variant with Ataxia-Telangiectasia/ATM-related cancers. 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: 22529920, 35264596, 33436325, 17124347, 35980532, 33779842, 19781682, 11443540, 39256447). ClinVar contains an entry for this variant (Variation ID: 127401). Based on the evidence outlined above, the variant was classified as uncertain significance.

Familial cancer of breast Uncertain:1 Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 22, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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].

Ataxia-telangiectasia syndrome Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 09, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inherited breast cancer and ovarian cancer Uncertain:1

Jul 23, 2025

Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_supporting, PM3_strong

ATM-related disorder Uncertain:1

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.5185G>C variant is predicted to result in the amino acid substitution p.Val1729Leu. This variant was identified in the lymphoblastoid cell line of an individual affected with ataxia telangiectasia (Table 4, Magliozzi et al. 2006. PubMed ID: 17124347). Additionally, this variant has been reported in the homozygous state in an individual with cerebellar ataxia; however, that individual also had a homozygous pathogenic variant in ATM, suggesting this variant is less likely to be a primary cause of disease (Table e2 - Coutelier et al. 2018. PubMed ID: 29482223). This variant was also identified in at least two presumably healthy individuals (Thorstenson et al. 2001. PubMed ID: 11443540; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant has been observed in ~0.1% of individuals in a population database and is reported in ClinVar with conflicting interpretations including likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127401/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Hereditary breast ovarian cancer syndrome Uncertain:1

Apr 02, 2025

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ClinGen ACMG ATM v1.3.0 criteria we chose this criterion: PM3 (strong pathogenic): Shalash (2021, PMID: 33779842): detected in two siblings with AT (Phenotype confident) --> 4P Coutelier (2018, PMID: 29482223): detected homozygous in patient also carrying hom NM_000051.3:c.9022C>T (ClinVar ID: 142187); reviewed through VCEP as likely pathogenic --> 0P

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.010	D
Polyphen		0.74	P
Vest4		0.47
MutPred		0.17		Loss of methylation at K1728 (P = 0.1413)
MVP		0.90
MPC		0.17
ClinPred		0.19	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.58
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs3092907; hg19: chr11-108172382; COSMIC: COSV53739151;