rs145119475

chr11-108287666-C-Achr11-108287666-C-Gchr11-108287666-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000051.4(ATM):c.4060C>A(p.Pro1354Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1354Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:10
• Conservation: PhyloP100: 1.50

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06936616).
• BP6: Variant 11-108287666-C-A is Benign according to our data. Variant chr11-108287666-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127379.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Likely_benign=5, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4060C>A	p.Pro1354Thr	missense_variant	27/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4060C>A	p.Pro1354Thr	missense_variant	27/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0000655

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: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000193 AC: 48 AN: 248752 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.000396

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000183 AC: 268 AN: 1461558 Hom.: 0 Cov.: 30 AF XY: 0.000160 AC XY: 116 AN XY: 727072

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000223

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74264

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000491

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ATM: PM2, BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 28779002, 33280026, 34299313, 20305132, 21787400, 26689913, 29522266, 30262796, 29684080, 28652578, 27913932, 31658756, 32854451, 35047863) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 17, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2022	- -

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 23, 2021	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.4060C>A (p.Pro1354Thr) variant has an allele frequency of 0.00018 (0.002%, 48/ 265,608 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00038 (0.04%, 44/115,626 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and Vest4 (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BP4 (PMID: 33280026). -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 16, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 21, 2023	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	Variant summary: ATM c.4060C>A (p.Pro1354Thr) 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 0.00019 in 248752 control chromosomes, predominantly at a frequency of 0.0004 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00019 vs 0.001), allowing no conclusion about variant significance. However, in certain European subpopulations the variant occurs with an even higher frequency, e.g. in Southern Europeans 0.0012 (14/11412 alleles), suggesting that the variant could be a benign polymorphism. In addition, the variant was reported in 6/7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). c.4060C>A has been reported in the literature in individuals affected with Breast Cancer and other tumor phenotypes, but was also repeatedly found in controls or non-cancer-related patient cohorts (e.g. Tavtigian_2009, Bernstein_2010, Tavera-Tapia_2017, Tiao_2017, Quezada Urban_2018, Urbina-Jara_2019, Kraemer_2019, Fanale_2020, Dorling_2021, Guglielmi_2021, Yu_2022), providing no strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as VUS (n=9), likely benign (n=3)/benign (n=1). 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	Jan 21, 2015	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

ATM-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2023

The ATM c.4060C>A variant is predicted to result in the amino acid substitution p.Pro1354Thr. This variant has been reported in individuals with a personal history of cancer (Lu et al. 2015. PubMed ID: 26689913, supplementary data 12) and has also been reported in an equal numbers of breast cancer cases and controls (Tavtigian et al. 2009. Table S2. PubMed ID: 19781682). In two other large cancer cohort studies, this variant was reported as a variant of uncertain significance (Quezada Urban et al. 2018. PubMed ID: 30262796, Supplementary Table 2; Fanale et al. 2020. PubMed ID: 32854451). It has been reported at frequencies up to ~0.04% in a large population database and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127379/). Although we suspect that this variant could be benign, at this time, its clinical significance is classified as uncertain due to the absence of conclusive functional and genetic evidence. -

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.Pro1354Thr variant was identified in a large-scale case control study in 1 of 5062 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer and was present in 1 of 4490 control chromosomes (frequency: 0.0002) from healthy individuals (Tavtigian-2009). The variant was identified in dbSNP (ID: rs145119475) as “With Uncertain significance” allele, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and University of Chicago). The variant was not identified in Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 50 of 274452 chromosomes at a frequency of 0.0002 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017) including 45 of 124128 European chromosomes and 1 of 6442 “other” chromosomes. The p.Pro1354Thr residue is not conserved in mammals, the threonine amino acid is found in mouse, African clawed frog, and zebrafish; and four out of five 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, HumanSpliceFinder) 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. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	18
Dann	Benign	0.88
Eigen	Benign	-0.024
Eigen_PC	Benign	0.096
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.76	T;T;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.069	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.69	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N;N;N;.
REVEL	Benign	0.057
Sift	Benign	0.41	T;T;T;.
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.25, 0.28
MVP		0.81
MPC		0.14
ClinPred		0.030	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs145119475; hg19: chr11-108158393; COSMIC: COSV104592312;