rs202173660

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000051.4(ATM):c.1444A>C(p.Lys482Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000065 in 1,614,208 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K482E) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:4

Conservation

PhyloP100: 4.38

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.102552325).

BP6

Variant 11-108250909-A-C is Benign according to our data. Variant chr11-108250909-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127338.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=13}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.1444A>C	p.Lys482Gln	missense_variant	10/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.1444A>C	p.Lys482Gln	missense_variant	10/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

251370

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135850

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:

0.000194

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000863

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000240

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000767

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 05, 2018	- -
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, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Lys482Gln variant was identified in 1 of 170 proband chromosomes (frequency: 0.006) from individuals or families with hereditary breast and ovarian cancer (Cock-Rada_2017). The p.Lys482Gln variant was also found in one study to be a recurrent variant in Mullerian adenosarcoma occurring in 3 of 36 chromosomes (frequency: 0.083) Howitt_2015). The variant was also identified in the following databases: dbSNP (ID: rs202173660) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (as uncertain significance by GeneDx, Ambry Genetics, Invitae, and Color Genomics), Clinvitae (3x), and Cosmic (1x in endometrial cancer). The variant was not identified in MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in control databases in 25 of 246152 chromosomes at a frequency of 0.000102 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 15302 chromosomes (freq: 0.000065), Other in 1 of 5482 chromosomes (freq: 0.000182), Latino in 1 of 33566 chromosomes (freq: 0.00003), European (Non-Finnish) in 22 of 111630 chromosomes (freq: 0.000197); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Lys482 residue is not 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast and colon cancers, as well both cases and controls in a breast cancer study (PMID: 28779002, 28135145, 25186627, 29522266, 34326862, 34399810, 34371384, 33471991, 36035419); This variant is associated with the following publications: (PMID: 28779002, 25231023, 25528188, 28528518, 28135145, 25186627, 28873162, 29522266, 28652578, 31159747, 31658756, 34399810, 34371384, 34803902, 36035419, 33471991, 34326862, 36980780) -

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	Jun 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 18, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Familial cancer of breast

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 03, 2023	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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 31, 2023	The ATM c.1444A>C (p.Lys482Gln) missense has a maximum subpopulation frequency of 0.017% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant was identified in an individual with breast and/or ovarian cancer undergoing multi-gene panel testing (PMID: 28528518). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Jun 20, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 14, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 02, 2020	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. -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 31, 2022	DNA sequence analysis of the ATM gene demonstrated two sequence changes in this gene. The first sequence change, c.1444A>C, in exon 10 results in an amino acid change, p.Lys482Gln. This sequence has been reported in individuals with breast, ovarian, and/or colorectal cancer (PMID: 28135145, 28528518, 33471991, 28779002, 34371384, 34399810) and has also been reported in healthy controls (PMID: 33471991, 28779002). This sequence change has been described in the gnomAD database with a frequency of 0.017% in the European subpopulation (dbSNP rs202173660). The p.Lys482Gln change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys482Gln substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Lys482Gln change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2024	Variant summary: ATM c.1444A>C (p.Lys482Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251370 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (9.5e-05 vs 0.001), additionally, this variant was also found in 1/7325 European Americans over the age of 70 without a history of cancer (FLOSSIES dataset). c.1444A>C has been reported in the literature in individuals affected with various types of cancer (HBOC, colorectal cancer, Mullerian adenosarcoma) without strong evidence for causality (Cock-Rada_2017, Yurgelun_2017, Howitt_2019, Tsaousis_2019, Urbina-Jara_2019, Mandelker_2017, Nunziato_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MUTYH c.849+3A>C, Nunziato_2022), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28528518, 25231023, 28873162, 36035419, 31159747, 31658756, 28135145). ClinVar contains an entry for this variant (Variation ID: 127338). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2024

The ATM c.1444A>C variant is predicted to result in the amino acid substitution p.Lys482Gln. This variant has been reported in individuals with colorectal, breast, or ovarian cancer (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; File S2, Howitt et al. 2014. PubMed ID: 25231023; Cock-Rada et al. 2018. PubMed ID: 28528518), but has also been reported in three healthy control individuals in a study of patients with chronic lymphocytic leukemia (Table S6, Tiao et al. 2017. PubMed ID: 28652578). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127338/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.086

.;T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

T;T;.

M_CAP

Benign

0.061

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.6

.;M;M

MutationTaster

Benign

0.78

N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.059

T;T;T

Sift4G

Uncertain

0.028

D;T;T

Polyphen

0.65

.;P;P

Vest4

0.33, 0.38

MVP

0.82

MPC

0.26

ClinPred

0.074

GERP RS

5.8

Varity_R

0.50

gMVP

0.22

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

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