NM_000051.4:c.3154-4G>A

Variant names:

• chr11-108272718-G-A
• rs199543313
• NM_000051.4:c.3154-4G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):​c.3154-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,613,642 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (4 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003800
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15
• Conservation: PhyloP100: 0.439
• Publications: 2 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-108272718-G-A is Benign according to our data. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254. Variant chr11-108272718-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142254.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000229 (334/1461600) while in subpopulation MID AF = 0.012 (69/5764). AF 95% confidence interval is 0.0097. There are 4 homozygotes in GnomAdExome4. There are 187 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.3154-4G>A		splice_region_variant, intron_variant	Intron 21 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3154-4G>A		splice_region_variant, intron_variant	Intron 21 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151924 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 251096 AF XY: 0.000228

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000229 AC: 334 AN: 1461600 Hom.: 4 Cov.: 32 AF XY: 0.000257 AC XY: 187 AN XY: 727108

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5764

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111856

Other (OTH) AF: 0.000331 AC: 20 AN: 60390

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74326

African (AFR) AF: 0.0000724 AC: 3 AN: 41462

American (AMR) AF: 0.000197 AC: 3 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67980

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000185

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Aug 07, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 25, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.3154-4G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 1613642 control chromosomes in the gnomAD database, including 4 homozygotes (gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00023 vs 0.004), however the presence of homozygotes in controls suggest the variant could be benign. c.3154-4G>A has been reported in the literature as a VUS in settings of multigene panel testing among in individuals undergoing testing for Lynch and/or associated cancers (example, Yurgelun_2015, Grant_2015, Tung_2014, Pereira_2022). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.1670T>G, p.Leu557X), providing supporting evidence for a benign role. 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: 25479140, 25186627, 25980754, 35980532, 34299313, 32658311). ClinVar contains an entry for this variant (Variation ID: 142254). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1 Benign:3

Mar 28, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BP4 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Jun 26, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 27, 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. -

Dec 10, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:1

Jan 10, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. 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]. -

Breast and/or ovarian cancer Uncertain:1

Apr 25, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.3154-4G>A variant was identified in 2 of 3100 proband chromosomes (frequency: 0.0006) from individuals or families with Lynch Syndrome and pancreatic cancer (Yurgelun 2015, Grant 2015). The variant was identified in dbSNP (rs199543313) as “with uncertain significance allele”, ClinVar (classified as likely benign by Invitae, Ambry Genetics and Color; as benign by GeneDx; and as uncertain significance by Integrated Genetics) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 53 of 282,472 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 7206 chromosomes (freq: 0.0004), European in 36 of 128962 chromosomes (freq: 0.0003), Ashkenazi Jewish in 2 of 10,358 chromosomes (freq: 0.0002), Latino in 6 of 35,420 chromosomes (freq: 0.0002), South Asian in 4 of 30,602 chromosomes (freq: 0.0001), and African in 2 of 24,920 chromosomes (freq: 0.00008), while it was not observed in the East Asian or Finnish populations. The c.3154-4G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions, nor does it affect positions -3 and -5 to -12, which are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, c.3154-4G>A is a non-highly conserved nucleotide and 4 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.4
DANN	Benign	0.38
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0040
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: rs199543313; hg19: chr11-108143445;