rs370240037

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000051.4(ATM):c.1440A>C(p.Leu480Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: -0.0620

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.1440A>C	p.Leu480Phe	missense_variant	Exon 10 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.1440A>C	p.Leu480Phe	missense_variant	Exon 10 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152218

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251354

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000800

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:3

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 480 of the ATM protein (p.Leu480Phe). This variant is present in population databases (rs370240037, gnomAD 0.004%). This missense change has been observed in individual(s) with ATM-related conditions (PMID: 19638463, 24448499, 26580448, 28779002, 33436325, 36029002). ClinVar contains an entry for this variant (Variation ID: 186322). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects ATM function (PMID: 36029002). 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. -

Jul 30, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L480F variant (also known as c.1440A>C), located in coding exon 9 of the ATM gene, results from an A to C substitution at nucleotide position 1440. The leucine at codon 480 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Kanchi KL et al. Nat. Commun. 2014;5:3156; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Decker B et al. J. Med. Genet., 2017 11;54:732-741). This alteration has also been identified in multiple individuals diagnosed with prostate cancer (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This alteration was 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. -

Oct 17, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with phenylalanine at codon 480 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 24448499, 26689913), chronic lymphocytic leukemia (PMID: 36029002), prostate cancer (PMID: 19638463, 33436325), and breast cancer (PMID: 28779002, 33471991). In a case-control study conducted in the UK, this variant was reported in 2/13087 breast cancer cases and 1/5488 controls (PMID: 28779002). In a second case-control study with international participation, this variant was reported in 3/60463 breast cancer cases and 2/53459 controls (PMID: 33471991). This variant has been identified in 6/282752 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 specified

Uncertain:1

Jan 06, 2025

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.1440A>C (p.Leu480Phe) 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 2e-05 in 252468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1440A>C has been reported in the literature in individuals affected with prostate cancer and individuals affected with other types of cancer (e.g. Pugh_2009, Karlsson_2021, Kanchi_2014, Lu_2015, Zhang_2015, Petrackova_2022). These reports do not provide unequivocal conclusions about association of the variant with prostate cancer or other ATM-related cancers. At least one publication reports experimental evidence evaluating the effect of the variant on protein function in CLL and T cells from an individual with chronic lymphocytic leukaemia who had the variant in the germline (Petrackova_2022). The most pronounced variant effect resulted in >50%-80% ATM activity versus the wildtype protein. The following publications have been ascertained in the context of this evaluation (PMID: 24448499, 33436325, 26689913, 19638463, 26580448, 36029002). ClinVar contains an entry for this variant (Variation ID: 186322). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Breast and/or ovarian cancer

Uncertain:1

May 11, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related disorder

Uncertain:1

May 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.1440A>C variant is predicted to result in the amino acid substitution p.Leu480Phe. This variant has been observed in an individual with ovarian cancer who also harbored a loss of function variant in the BRCA1 gene (Kanchi et al. 2014. PubMed ID: 24448499) and another individual with prostate cancer (Pugh et al. 2009. PubMed ID: 19638463). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186322/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Jul 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with ovarian, breast, or prostate cancer (PMID: 19638463, 24448499, 26689913, 28779002, 32832836, 33436325); This variant is associated with the following publications: (PMID: 19638463, 26689913, 24448499, 28779002, 26580448, 32832836, 33436325, 36029002, 33471991) -

Familial cancer of breast

Uncertain:1

Feb 05, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.096

.;T;T

Eigen

Benign

-0.0091

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.81

T;T;.

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.7

.;M;M

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.2

N;N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.014

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.85, 0.81

MutPred

0.31

Gain of MoRF binding (P = 0.1027);Gain of MoRF binding (P = 0.1027);Gain of MoRF binding (P = 0.1027);

MVP

0.89

MPC

0.60

ClinPred

0.92

GERP RS

-3.1

Varity_R

0.22

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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