rs370282831

chr11-108272743-G-Achr11-108272743-G-Cchr11-108272743-G-T

Variant summary

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

The NM_000051.4(ATM):c.3175G>A(p.Ala1059Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. A1059S) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 2.73

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=0.24541804).

BP6

Variant 11-108272743-G-A is Benign according to our data. Variant chr11-108272743-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127367.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.3175G>A	p.Ala1059Thr	missense_variant	22/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.3175G>A	p.Ala1059Thr	missense_variant	22/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152066

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:

0.00000398

AC:

AN:

251282

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135836

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000989

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74274

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:

0.0000564

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

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	Dec 13, 2021	This missense variant replaces alanine with threonine at codon 1059 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 an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 1/53460 controls (OR=0.442, 95%CI 0.015 to 13.178, p-value=0.469; PMID: 33471991). This variant has also been identified in 3/282670 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	Oct 12, 2022	The p.A1059T variant (also known as c.3175G>A), located in coding exon 21 of the ATM gene, results from a G to A substitution at nucleotide position 3175. The alanine at codon 1059 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in 0/13087 breast cancer cases and 1/5488 control individuals in the UK (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This amino acid position is 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. -

Familial cancer of breast

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 23, 2024	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]. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 06, 2023

Variant summary: ATM c.3175G>A (p.Ala1059Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-06 in 262258 control chromosomes (gnomAD, Decker_2017). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3175G>A has been reported in the literature in individuals affected with Breast Cancer, Lynch Syndrome and Chronic Lymphocytic Leukemia (e.g. Bernstein_2010, Vollbrecht_2015, Yurgelun_2015) but it was also reported in controls (e.g. Decker_2017, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or Breast Cancer. 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: 20305132, 28779002, 29778231, 28652578, 26053404, 25980754, 33471991). Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely benign. 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

May 23, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast cancer, Lynch syndrome-associated cancer and/or polyps, or CLL, and also seen in unaffected controls (Bernstein et al., 2010; Vollbrecht et al., 2015; Yurgelun et al., 2015; Decker et al., 2017; Tiao et al., 2017); This variant is associated with the following publications: (PMID: 25980754, 28779002, 28652578, 29778231, 19781682, 25356970, 32055024, 26053404, 20305132) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

May 14, 2018

This sequence variant is a single nucleotide substitution (G>A) that results in an alanine to threonine amino acid change at residue 1059 in the ATM protein. This is a previously reported, rare variant in a control population dataset (gnomAD database, 3/277,044 alleles, 0.0011% overall frequency) that has been observed in at least one individual with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). The Ala1059 residue is not located within a domain typically recognized as critical for ATM function in the DNA mismatch repair pathway. Bioinformatic tools queried are in disagreement with whether this alanine to threonine amino acid substitution would be damaging. The alanine residue at this position is only moderately evolutionarily conserved across mammalian species examined. All six ClinVar entries for this variant report the significance of this variant to be uncertain. Based upon the evidence, we also consider this to be a variant of uncertain significance. -

Ataxia-telangiectasia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.0065

BayesDel_noAF

Benign

-0.25

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.73

T;T;.

M_CAP

Benign

0.084

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.65

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.084

.;B;B

Vest4

0.20, 0.22

MVP

0.84

MPC

0.14

ClinPred

0.56

GERP RS

4.7

Varity_R

0.39

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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