rs56399311

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 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).

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:13B:1

Conservation

PhyloP100: 8.59

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:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5882A>G	p.Tyr1961Cys	missense_variant	39/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.5882A>G	p.Tyr1961Cys	missense_variant	39/63		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

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251076

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135708

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000729

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000580

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:13Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 23, 2024	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. -

Familial cancer of breast

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 23, 2024	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:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 22, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2023	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 (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). 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). In a large case-control study, this variant was reported in 5/60461 breast cancer cases and 2/53459 controls (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 17, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 09, 2024	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. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 30, 2024

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) -

Breast carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 26, 2021

_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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over