rs149636614

chr11-108248940-A-Gchr11-108248940-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000051.4(ATM):c.1073A>G(p.Asn358Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,605,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N358T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:12
• Conservation: PhyloP100: 1.17

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008295089).
• BP6: Variant 11-108248940-A-G is Benign according to our data. Variant chr11-108248940-A-G is described in ClinVar as [Benign]. Clinvar id is 127329.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-108248940-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000716 (109/152208) while in subpopulation AFR AF= 0.00248 (103/41528). AF 95% confidence interval is 0.00209. There are 1 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.1073A>G	p.Asn358Ser	missense_variant	9/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.1073A>G	p.Asn358Ser	missense_variant	9/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 109 AN: 152096 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000159 AC: 39 AN: 246050 Hom.: 0 AF XY: 0.000128 AC XY: 17 AN XY: 133234

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.0000889

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.0000771 AC: 112 AN: 1453586 Hom.: 0 Cov.: 32 AF XY: 0.0000760 AC XY: 55 AN XY: 723290

Gnomad4 AFR exome AF: 0.00222

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152208 Hom.: 1 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74432

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000374 Hom.: 0

Bravo AF: 0.000869

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2018	This variant is denoted ATM c.1073A>G at the cDNA level, p.Asn358Ser (N358S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). ATM Asn358Ser was reported in an individual with breast cancer, in an individual with a personal history of a Lynch syndrome-related cancer and/or colon polyps, and in an individual undergoing multigene hereditary cancer panel testing (Yurgelun 2015, Mu 2016, Decker 2017). This variant was observed at an allele frequency of 0.23% (55/23,886) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Asn358Ser is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Asn358Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 01, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 06, 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. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2024	Variant summary: ATM c.1073A>G (p.Asn358Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 1605794 control chromosomes, predominantly at a frequency of 0.0024 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1073A>G has been reported in the literature in individuals affected with Breast Cancer (e.g. Decker_2017) and Lynch Syndrome (e.g. Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 27621404, 28779002, 27720647, 30541756, 28652578, 25980754, 31206626). ClinVar contains an entry for this variant (Variation ID: 127329). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 02, 2015	- -

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

Oct 03, 2019

- -

Ataxia-telangiectasia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

ATM-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2022

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). -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Asn358Ser variant was identified in 1 of 562 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and triple-negative breast cancer and was present in 2 of 488 control chromosomes (frequency: 0.004) from healthy individuals (Lovejoy 2018, Rosenstein 2006). The variant was also identified in dbSNP (ID: rs149636614) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and Integrated Genetics and as uncertain significance by GeneDx, Invitae, University of Chicago and EGL Genetic Diagnostics), LOVD 3.0 (classified as likely benign by VKGL data sharing initiative). The variant was identified in control databases in 60 of 272346 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 55 of 23886 chromosomes (freq: 0.002), Other in 1 of 6350 chromosomes (freq: 0.0002), Latino in 3 of 33660 chromosomes (freq: 0.00009), European Non-Finnish in 1 of 125094 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asn358 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Familial cancer of breast Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Mar 09, 2022

The ATM c.1073A>G (p.Asn358Ser) variant has a gnomAD v2.1.1 filtering allele frequency of 0.1523% (African/African-American; exomes) which exceeds the ATM BS1 threshold of 0.05% (BS1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 500031, 61756). In silico protein predictors (ALIGN GVGD: Class C0; REVEL: 0.054; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.13/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 10.82, variant = 10.82)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Benign	0.29
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.71	T;T;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.054
Sift	Benign	0.72	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.085, 0.080
MVP		0.66
MPC		0.097
ClinPred		0.018	T
GERP RS		1.0
Varity_R		0.058
gMVP		0.088

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs149636614; hg19: chr11-108119667;