NM_000051.4:c.295A>G

Variant names:

• chr11-108229287-A-G
• rs137882485
• NM_000051.4:c.295A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000051.4(ATM):​c.295A>G​(p.Ser99Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,598 control chromosomes in the GnomAD database, including 1 homozygotes. 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. S99R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:8
• Conservation: PhyloP100: 6.84
• Publications: 16 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

Y_RNA (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021582246).
• BP6: Variant 11-108229287-A-G is Benign according to our data. Variant chr11-108229287-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127364.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.295A>G	p.Ser99Gly	missense_variant	Exon 4 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.295A>G	p.Ser99Gly	missense_variant	Exon 4 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 250934 AF XY: 0.000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1461440 Hom.: 1 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.000626 AC: 28 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111746

Other (OTH) AF: 0.000249 AC: 15 AN: 60360

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.000459 AC: 7 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 2 AN: 3472

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PM2

Jul 18, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1

Feb 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with breast cancer, prostate cancer, or chronic lymphocytic leukemia, but also in healthy controls (Lahdesmaki 2004, Tavtigian 2009, Tung 2015, Decker 2017, Tiao 2017, Hauke 2018, Girard 2019, Karlsson 2021); 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: 30303537, 19781682, 14754616, 26787654, 28873162, 28652578, 28779002, 25186627, 29522266, 29684080, 31552911, 33436325)

Dec 26, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

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.Ser99Gly variant was identified in 3 of 7786 proband chromosomes (frequency: 0.0004) from individuals or families with B-chronic lymphocytic leukemia or breast cancer and was not identified in 6732 control chromosomes from healthy individuals (Lähdesmäki 2004, Tavtigian 2009, Young 2016). The variant was also identified in dbSNP (ID: rs137882485) as "With Uncertain significance allele" and ClinVar (classified as likely benign by Invitae; and as uncertain significance by Ambry Genetics, GeneDx, and five other submitters). The variant was not identified in the COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 71 of 276750 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 39 of 10144 chromosomes (freq: 0.004), Other in 5 of 6464 chromosomes (freq: 0.0008), Latino in 23 of 34384 chromosomes (freq: 0.0007), and European in 4 of 126388 chromosomes (freq: 0.00003); it was not observed in the African, East Asian, Finnish, or South Asian populations. The p.Ser99 residue is 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. One study suggested a non-pathogenic role for this variant (Lähdesmäki 2004). 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.

Ataxia-telangiectasia syndrome Uncertain:3 Benign:1

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Apr 17, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Dec 01, 2017

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 12, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Jan 29, 2021

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.

Mar 05, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1 Benign:1

Sep 26, 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.295A>G (p.Ser99Gly) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 1638634 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00011 vs 0.004), allowing no conclusion about variant significance. c.295A>G has been reported in the literature in individuals affected with Breast Cancer (examples: Tavtigian_2009, Tung_2015, Girard_2019), but also in healthy controls (examples: Tiao_2017, Girard_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. At-least two co-occurrences with other pathogenic variants have been observed in our laboratory (BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161fs; MSH2 c.942+3A>T), providing supporting evidence for a benign role. In addition, a recent case-control study showed that this variant was not associated with breast cancer (Dorling_2021). The following publications have been ascertained in the context of this evaluation (PMID: 19781682, 25186627, 14754616, 26787654, 28873162, 28652578, 30303537, 33471991, 30883245, 34262154, 35309086, 35264596, 33436325, 31206626). These report(s) do not provide unequivocal conclusions about association of the variant with ATM-related conditions. 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: 30883245, 34262154, 33471991, 35309086, 30303537, 35264596, 33436325, 14754616, 28873162, 19781682, 28652578, 25186627, 31206626, 26787654). ClinVar contains an entry for this variant (Variation ID: 127364). Based on the evidence outlined above, the variant was classified as likely benign.

Dec 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.295A>G, in exon 4 that results in an amino acid change, p.Ser99Gly. This sequence change has been described in the gnomAD database with a frequency of 0.38% in the Ashkenazi Jewish subpopulation (dbSNP rs137882485). The p.Ser99Gly change affects a highly 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.Ser99Gly substitution. The Ser99Gly change has been identified in individuals with breast cancer, prostate cancer, and chronic lymphocytic leukemia (PMID: 19781682, 33436325, 28652578). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser99Gly change remains unknown at this time.

Familial cancer of breast Uncertain:1 Benign:1

Apr 18, 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].

Jul 01, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM-related disorder Benign:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T;T;.;T;T;T;T;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
LIST_S2	Benign	0.80	T;T;T;T;.;.;.;.;.;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.0	.;M;.;.;M;.;.;.;.;.
PhyloP100		6.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;N;D;.;N;.;.;.;.;.
Sift	Benign	0.050	D;T;T;.;T;.;.;.;.;.
Sift4G	Uncertain	0.057	T;T;T;T;T;.;.;.;T;T
Vest4		0.0
ClinPred		0.11	T
GERP RS		6.1
Varity_R		0.44
gMVP		0.33
Mutation Taster		=69/31	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: rs137882485; hg19: chr11-108100014;