rs786203765

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000051.4(ATM):c.5938G>A(p.Gly1980Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000097 in 1,443,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.39

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16153917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5938G>A	p.Gly1980Arg	missense_variant	40/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.5938G>A	p.Gly1980Arg	missense_variant	40/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251186

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000970

AC:

AN:

1443276

Hom.:

Cov.:

AF XY:

0.00000834

AC XY:

AN XY:

719096

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:

0.0000128

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000602

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2022	This missense variant replaces glycine with arginine at codon 1980 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. In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has also been reported in an individual affected with multiple adenomatous polyps (PMID: 25938944). This variant has been identified in 2/251186 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	Ambry Genetics	May 05, 2023	The p.G1980R variant (also known as c.5938G>A), located in coding exon 39 of the ATM gene, results from a G to A substitution at nucleotide position 5938. The glycine at codon 1980 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and in 1/51 patients with multiple colorectal adenomas who underwent whole exome sequencing (Weren RD et al. Nat Genet, 2015 Jun;47:668-71). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ataxia-telangiectasia syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1980 of the ATM protein (p.Gly1980Arg). This variant is present in population databases (rs786203765, gnomAD 0.002%). This missense change has been observed in individual(s) with colon polyps and with breast cancer and/or ovarian cancer (PMID: 25938944, 29522266). ClinVar contains an entry for this variant (Variation ID: 187479). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Oct 02, 2018

This sequence variant is a single nucleotide substitution (G>A) that results in a glycine to arginine amino acid change at residue 1980 in the ATM protein. This is a rare variant, and has been observed in the gnomAD database at a frequency of 0.00001792 (2/111586 alleles). The variant has additionally been observed in a BRCA1/2-negative breast cancer case (PMID 29522266), a breast cancer case identified in the Breast Cancer Family Registry (PMID 21787400), and a case with multiple adenomatous polyps (PMID 25938944). This variant alters an amino acid residue found within the FAT (FRAP-ATM-TRRAP) domain of the ATM protein. Bioinformatic tools queried are inconsistent in their predictions of the pathogenicity of this variant, and the glycine residue at this position in the ATM protein is poorly conserved among mammalian species. There are no functional studies determining the effect of this variant on protein structure and function, to our knowledge. Though there are no published reports strongly linking this variant to disease to date, there is insufficient evidence at this time to fully assess if this variant is pathogenic or benign. Thus, it is a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.068

T;T

Eigen

Benign

0.048

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

D;.

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.11

Sift

Benign

0.43

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.011

B;B

Vest4

0.33

MutPred

0.37

Gain of solvent accessibility (P = 0.0971);Gain of solvent accessibility (P = 0.0971);

MVP

0.91

MPC

0.16

ClinPred

0.36

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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