rs34640941

chr11-108289789-A-Gchr11-108289789-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000051.4(ATM):c.4424A>G(p.Tyr1475Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000974 in 1,612,680 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. Y1475D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00054 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:13
• Conservation: PhyloP100: 3.91

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 -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.07898763).
• BP6: Variant 11-108289789-A-G is Benign according to our data. Variant chr11-108289789-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127392.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Likely_benign=9, Benign=2}. Variant chr11-108289789-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4424A>G	p.Tyr1475Cys	missense_variant	29/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4424A>G	p.Tyr1475Cys	missense_variant	29/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000600 AC: 150 AN: 250206 Hom.: 0 AF XY: 0.000577 AC XY: 78 AN XY: 135270

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.000946

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.00102 AC: 1489 AN: 1460346 Hom.: 0 Cov.: 31 AF XY: 0.000953 AC XY: 692 AN XY: 726494

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000956

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.000813

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74496

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.000955

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000903 Hom.: 0

Bravo AF: 0.000518

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.00125

EpiControl AF: 0.000890

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:4 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 03, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 15, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not specified Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 05, 2024	Variant summary: ATM c.4424A>G (p.Tyr1475Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00098 in 1614758 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD (v4.0.0) database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than 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 Non-Finnish European origin. In addition, this variant has been reported in 16/7325 European American women, who are older than age 70 and cancer free (in the FLOSSIES database). Multiple publications cite the variant in sequencing studies of affected individuals with varying tumor phenotypes, including breast-, pancreatic- and prostate cancer, lymphoma and Lynch Syndrome, although with limited information (i.e. lack of co-occurrence and cosegregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia-Telangiectasia. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.1861C>T, p.Arg621X, internal testing), providing supporting evidence for a benign role. To our knowledge, no publication reported experimental evidence evaluating an impact on protein function. The following publications have been ascertained in the context of this evaluation (PMID: 17344846, 23555315, 25980754, 16167060, 19781682, 17640065, 20305132, 17333338, 16832357, 16914028, 12697903, 25479140, 12935922, 25862857, 26787654, 26898890, 26976419, 23369113, 27978560, 28652578, 27782108). ClinVar contains an entry for this variant (Variation ID: 127392). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 30, 2020	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.4424A>G, in exon 29 that results in an amino acid change, p.Tyr1475Cys. This sequence change has been described in the gnomAD database with a frequency of 0.1% in the Finnish sub-population (dbSNP rs34640941). The p.Tyr1475Cys change has been identified in a female with breast cancer (PMID: 26976419) and in an individual with colon cancer (PMID: 27978560). The p.Tyr1475Cys change affects a poorly conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Tyr1475Cys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Tyr1475Cys change remains unknown at this time. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 02, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 29, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 26, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 20, 2022	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ATM: PM2, BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2017	The p.Tyr1475Cys variant (rs34640941) has not been reported association with ataxia telangiectasia in the medical literature or gene specific variation databases but has been reported to ClinVar (Variation ID: 127392). However, the p.Tyr1475Cys variant has been identified in numerous cancer sequencing cohorts in both case and controls (Fang 2003, Meier 2005, Sipahimalani 2007, Sommer 2003, Tavtigian 2009, Tommiska 2006 and Yurgelun 2015). In a large meta-analysis of breast cancer studies, Tavtigian et al. identified the p.Tyr1475Cys variant in 1/4112 breast cancer cases and 6/2399 controls. Based on these observations the p.Tyr1475Cys variant is likely to be benign. -

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

Jul 30, 2021

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

ATM NM_000051.3 exon 29 p.Tyr1475Cys (c.4424A>G): This variant has been reported in the literature as germline in at least 6 individuals with various types of cancer (breast, colon, lymphoma) (Sipahimalani 2007 PMID:17640065, Tavtigian 2009 PMID:19781682, Yurgelun 2015 PMID:19781682, Tung 2016 PMID:26976419, Pearlman 2017 PMID:27978560). However, this variant has also been identified in controls (Tavtigian 2009 PMID:19781682) and is present in 0.1% (26/25072) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-108160516-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:127392). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

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.Tyr1475Cys variant was identified in 4 of 1802 proband chromosomes (frequency: 0.002) from African-American, American, Finnish, Dutch and German individuals or families with breast cancer (unselected for history) or childhood acute lymphocytic leukemia; and was present in 1 of 856 control chromosomes (frequency: 0.001) from healthy individuals (Hirsch 2008, Tung 2016, Tommiska 2006, Meier 2005). The variant was also identified in the following databases: dbSNP (ID: rs34640941) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity, sumbitters: uncertain significance by GeneDx; likely benign by Invitae and Ambry Genetics), Clinvitae (3x), Cosmic (1x in a diffuse large b cell lymphoma) and was not identified in the COGR, MutDB, LOVD 3.0 or ATM-LOVD databases. The variant was identified in control databases in 152 of 276060 chromosomes at a frequency of 0.0006 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). It was identified in the following populations: African in 5 of 23840 chromosomes (frequency: 0002), Other in 4 of 6426 chromosomes (frequency: 0006), Latino in 10 of 34336 chromosomes (frequency: 0003), European Non-Finnish in 109 of 126152 chromosomes (frequency: 0.0009), and European Finnish in 24 of 25740 chromosomes (frequency: 005). The p.Tyr1475 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, 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. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Division of Medical Genetics, University of Washington

Jan 03, 2019

This variant has been reported in individuals with breast cancer (Tung 2016, Tommiska 2006), as well as control populations (Hirsch 2008, Sommer 2003). The c.4424A>G variant has an overall allele frequency of 0.0006 in the Genome Aggregation Database (gnomad.broadinstitute.org). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. -

ATM-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

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	0.072
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T;.;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.079	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	M;M;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.0	D;D;.
REVEL	Uncertain	0.30
Sift	Benign	0.085	T;T;.
Sift4G	Benign	0.090	T;T;D
Polyphen		0.87	P;P;.
Vest4		0.35
MVP		0.91
MPC		0.16
ClinPred		0.12	T
GERP RS		3.1
Varity_R		0.34
gMVP		0.51

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: rs34640941; hg19: chr11-108160516; COSMIC: COSV53763152; COSMIC: COSV53763152;