rs56399311

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000051.4(ATM):c.5882A>G(p.Tyr1961Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y1961Y) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:19B:1

Conservation

PhyloP100: 8.59

Publications

19 publications found

Variant links:

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 links:

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.5882A>G	p.Tyr1961Cys	missense_variant	Exon 39 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.5882A>G	p.Tyr1961Cys	missense_variant	Exon 39 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251076

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1461302

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.0000224

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000729

AC:

AN:

1111708

Other (OTH)

AF:

0.0000663

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000504

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:19Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:4Benign:1

Jan 31, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 16, 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. -

May 23, 2024

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.5882A>G (p.Tyr1961Cys) variant has a classification of uncertain for Ataxia Telangiectasia (AT) as there is limited evidence regarding the association with this variant and AT in homozgyous or compound heterozygous individuals. However, this variant has been found to be associated with more severe personal and family histories of cancer and is therefore classified as likely pathogenic for hereditary cancer risk. Please note: this variant was assessed in the context of healthy population screening. -

Jul 02, 2018

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Pathogenic:1Uncertain:3

Jun 06, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

a variant of uncertain significance in the ATM gene (p.Tyr1961Cys). This sequence change replaces tyrosine with cysteine at codon 1961 of the ATM protein (p.Tyr1961Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs56399311, gnomAD 0.004%). This variant has been observed in individuals affected with prostate cancer, pancreatic cancer, chronic lymphocytic leukemia, and T-cell lymphoblastic leukemia (PMID: 25479140, 9622061, 21933854, Invitae). However, in one of these individuals’ pathogenic alleles were also identified in ATM, which suggests that this c.5882A>G variant was not the primary cause of disease. ClinVar contains 9 entries for this variant (Variation ID: 127413), all of which interpreted this variant as of uncertain significance. This variant has been predicted as damaging by Polyphen and SIFT. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 16, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 13, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2024

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.5882A>G (p.Tyr1961Cys) variant is considered likely pathogenic for hereditary cancer risk. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic ATM variants [PMID: 25085752]. However, at this time, it is unclear whether homozygous or compound heterozygous inheritance of this variant causes the recessive condition ataxia telangiectasia (AT). -

Hereditary cancer-predisposing syndrome

Uncertain:4

Sep 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y1961C variant (also known as c.5882A>G), located in coding exon 38 of the ATM gene, results from an A to G substitution at nucleotide position 5882. The tyrosine at codon 1961 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a patient with CLL and was shown to confer reduced, but not absent ATM kinase activity in in vitro studies (Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). This alteration has also been reported in breast and pancreatic cancer patients (Grant RC et al. Gastroenterology, 2015 Mar;148:556-64; Young EL et al. J. Med. Genet., 2016 06;53:366-76; Decker B et al. J. Med. Genet., 2017 11;54:732-741; Chaffee KG et al. Genet. Med., 2018 01;20:119-127; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Germani A et al. J Clin Med, 2020 Sep;9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Aug 01, 2018

GeneKor MSA

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 03, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_Supporting c.5882A>G, located in exon 39 of the ATM gene, is predicted to result in the substitution of tyrosine by cysteine at codon 1961, p.(Tyr1961Cys). This variant is found in 9/117911 at a filtered allele frequency of 0.004% in the gnomAD v2.1.1 database (European non-Finnish non-cancer data set). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score (0.611) for this variant is indeterminate regarding the effect that it may have on protein function. A functional study has shown reduced kinase activity (PMID: 19431188)(PS3_Supporting). In addition, the variant was also identified in ClinVar (12x uncertain significance, 1x likely benign) and in the LOVD (2x uncertain significance, 2x not provided) databases. Based on currently available information, the variant c.5882A>G is classified as an uncertain significance variant according to ClinGen-ATM Guidelines version v1.1. -

Jan 13, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces tyrosine with cysteine at codon 1961 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. A functional study has shown that the variant results in reduced ATM kinase activity in a cell line-based assay (PMID: 19431188). This variant has been reported in individuals affected with breast or pancreatic cancer (PMID: 25479140, 28726808, 28779002, 38354330). In a large case-control study, this variant was reported in 5/60461 breast cancer cases and 2/53459 controls (PMID: 33471991). This variant has also been identified in 10/251076 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:3

Feb 19, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with breast cancer, pancreatic cancer, prostate cancer, and various forms of leukemia (PMID: 21933854, 25479140, 28779002, 28726808, 32957588, 33436325, 35672297); Published functional studies suggest a damaging effect: reduced kinase activity (PMID: 19431188); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21933854, 22529920, 9622061, 16014569, 26787654, 27720647, 25479140, 28779002, 28726808, 25741868, 28652578, 17344846, 34426522, 32957588, 31159747, 30303537, 33436325, 35672297, 19431188, 26837699, 23532176, 34262154) -

Jun 19, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.5882A>G; p.Tyr1961Cys variant (rs56399311; ClinVar ID: 127413) is reported in the literature in several individuals affected with breast cancer or leukemia, although its clinical significance was not demonstrated (Barone 2009, Decker 2017, Girard 2019, Royo 2022). This variant is found in the general population with an overall allele frequency of 0.004% (10/251,076 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.611), although functional studies suggest the variant has reduced kinase activity (Barone 2009). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Barone G et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009 Aug;30(8):1222-30. PMID: 19431188. Decker B et al. Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. J Med Genet. 2017 Nov;54(11):732-741. PMID: 28779002. Girard E et al. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. Int J Cancer. 2019 Apr 15;144(8):1962-1974. PMID: 30303537. Royo R et al. ATM germline variants in a young adult with chronic lymphocytic leukemia: 8?years of genomic evolution. Blood Cancer J. 2022 Jun 7;12(6):90. PMID: 35672297. -

not specified

Uncertain:2

Sep 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATM c.5882A>G (p.Tyr1961Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251076 control chromosomes, predominantly at a frequency of 7.9e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in multiple patients with CLL, breast cancer, or pancreatic cancer, without strong evidence supporting pathogenicity of this variant (Luo_1998, Austen_2005, Greenman_2007, Skowronska_2011, Grant_2015, Young_2015, Chaffee_2018, Girard_2019, Tsaousis_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One publication lists the variant as having reduced ATM Kinase activity but does not provide data supporting this statement (Barone_2009). The following publications have been ascertained in the context of this evaluation (PMID: 16014569, 19431188, 28726808, 30303537, 25479140, 17344846, 9622061, 26837699, 21933854, 28652578, 31159747, 26787654). ClinVar contains an entry for this variant (Variation ID: 127413). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jul 17, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cancer or benign tumor

Uncertain:1

Apr 24, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast carcinoma

Uncertain:1

Nov 26, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_ Criteria applied: PM2_SUP, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;.

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

8.6

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.95

MVP

0.97

MPC

0.65

ClinPred

0.89

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.66

gMVP

0.76

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over