rs140856217

Positions:

• chr11-108293410-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000051.4(ATM):​c.4709T>C​(p.Val1570Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,612,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:19
• Conservation: PhyloP100: 1.04

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03293863).
• BP6: Variant 11-108293410-T-C is Benign according to our data. Variant chr11-108293410-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127394.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=10, Benign=5}. Variant chr11-108293410-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.4709T>C	p.Val1570Ala	missense_variant	31/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4709T>C	p.Val1570Ala	missense_variant	31/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152136 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000410 AC: 103 AN: 250980 Hom.: 0 AF XY: 0.000391 AC XY: 53 AN XY: 135650

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000723

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000387 AC: 565 AN: 1459806 Hom.: 0 Cov.: 30 AF XY: 0.000365 AC XY: 265 AN XY: 726414

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000466

Gnomad4 OTH exome AF: 0.000299

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152254 Hom.: 0 Cov.: 30 AF XY: 0.000403 AC XY: 30 AN XY: 74460

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000527 Hom.: 2

Bravo AF: 0.000355

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000486 AC: 59

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:19

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:7

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ATM: PM2, BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2018	This variant is denoted ATM c.4709T>C at the cDNA level, p.Val1570Ala (V1570A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant has been reported in several individuals with breast cancer, one with prostate cancer, and at least one with advanced cancer of unspecified type, as well as in an individual with a personal history of a Lynch syndrome-related cancer and/or polyps (Izatt 1999, Dork 2001, Pugh 2009, Tavtigian 2009, Yurgelun 2015, Maxwell, 2016, Tung 2016, Mandelker 2017). In one family, the variant was identified in both a proband with early onset breast cancer and her mother, who also had a history of breast cancer (Izatt 1999). ATM Val1570Ala was observed at an allele frequency of 0.07% (91/126,354) in individuals of European ancestry in large population cohorts (Lek 2016). This variant 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 Val1570Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 01, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 13, 2022	- -

Ataxia-telangiectasia syndrome Uncertain:3 Benign:4

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. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 06, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 13, 2022	Variant summary: ATM c.4709T>C (p.Val1570Ala) 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 0.00041 in 251524 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00041 vs 0.001), allowing no conclusion about variant significance. c.4709T>C has been reported in the literature as a VUS/likely benign variant in settings of multigene panel testing on individuals affected with various cancer phenotypes (e.g. Izatt, 1999, Dork_2001, Gumy-Pause_2006, Bernstein_2010, Haiman_2013, Maxwell_2016, Grasel_2020, Bandeira_2021) without strong evidence for causality. One of these studies reported this variant within settings of loss of heterozygosity (LOH) of the normal allele in a family where it did not clearly segregate with cancer (Grasel_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/ATM-related cancers. At-least one co-occurrence with another pathogenic variant(s) have been observed at our laboratory (BRCA2 c.9097dupA, p.Thr3033fsX11), providing supporting evidence for a benign role. 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. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=7; VUS, n=10). Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. At-least one submitter reports a non-specified co-occurrence with mutation in same gene (phase unknown) as a basis of their likely benign classification. Based on the evidence outlined above, the variant was classified as benign. -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 07, 2024	- -

Familial cancer of breast Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 27, 2020	This variant was classified as: Uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 20, 2024	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]. -

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

May 05, 2023

- -

ATM-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2024

The ATM c.4709T>C variant is predicted to result in the amino acid substitution p.Val1570Ala. This variant has been reported in at least one study to segregate with breast cancer in a first-degree relative of the proband (Table 3, Izatt et al. 1999. PubMed ID: 10534763). It has also been reported in several individuals with a history of breast cancer (Dörk et al. 2001. PubMed ID: 11606401; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Tung et al. 2016. PubMed ID: 26976419), as well as in an individual with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754), but was classified as a variant of uncertain significance. It was also found as a recurring variant in patients with chronic lymphocytic leukemia (Tiao et al. 2017. PubMed ID: 28652578) as well as in individuals with pancreatic ductal adenocarcinoma (Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.073% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127394/). At this time, we classify the clinical significance of this variant as uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Val1570Ala variant was identified in 7 of 12586 proband chromosomes (frequency: 0.0005) from U.S., Canadian, German and British individuals or families with breast cancer, Lynch syndrome or prostate cancer and was not identified in 4998 control chromosomes from healthy individuals (Tavtigian 2009, Tung 2016, Izzat 2009, Dork 2001, Yurgelin 2015, Pugh 2009). The variant was also identified in dbSNP (ID: rs140856217) as “With Uncertain significance allele”, ClinVar and Clinvitae (1x classified as likely benign by Ambry Genetics, 2x uncertain significance by GeneDx and Invitae). The variant was not identified in the COGR, COSMIC, MutDB, or the LOVD 3.0 databases. The variant was identified in control databases in 112 of 276738 chromosomes at a frequency of 0.0004 in the following populations: European non-Finnish 91 of 126354 chromosomes (freq. 0.0007); “Other” in 3 of 6464 chromosomes (freq. 0.0005); Latino in 15 of 34400 chromosomes (freq. 0.0004); European Finnish in 2 of 25720 chromosomes (freq. 0.00008); African in 1 of 24028 chromosomes (freq. 0.00004) (Genome Aggregation Consortium Feb 27, 2017). This variant was found in one British individual with: two separate primary early-onset breast cancers, segregation with one family member with breast cancer (mother), loss of heterozygosity for ATM and neighbouring loci in tumour DNA, and sensitivity reaction to radiotherapy, however the authors conclude that this may represent a rare polymorphism because the residue is not conserved in mouse and they did not perceive that the variant was found in a functional domain (Izzat 2009). The p.Val1570Ala 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.073	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.65	T;.
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.46	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.15
Sift	Benign	0.76	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.0	B;B
Vest4		0.025
MVP		0.96
MPC		0.15
ClinPred		0.013	T
GERP RS		4.2
Varity_R		0.048
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140856217; hg19: chr11-108164137; COSMIC: COSV104592340; COSMIC: COSV104592340;