rs146382972

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000051.4(ATM):c.334G>A(p.Ala112Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000146 in 1,604,732 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:9

Conservation

PhyloP100: 5.35

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016045034).

BP6

Variant 11-108235672-G-A is Benign according to our data. Variant chr11-108235672-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127370.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=4, Uncertain_significance=4}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000722 (110/152254) while in subpopulation AFR AF= 0.00248 (103/41552). AF 95% confidence interval is 0.00209. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.334G>A	p.Ala112Thr	missense_variant, splice_region_variant	5/63	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.334G>A	p.Ala112Thr	missense_variant, splice_region_variant	5/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.000730

AC:

111

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000208

AC:

AN:

250218

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00280

Gnomad AMR exome

AF:

0.000203

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000861

AC:

125

AN:

1452478

Hom.:

Cov.:

AF XY:

0.0000678

AC XY:

AN XY:

723078

show subpopulations

Gnomad4 AFR exome

AF:

0.00280

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152254

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000159

Hom.:

Bravo

AF:

0.000865

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2020	This variant is associated with the following publications: (PMID: 25318351, 25980754, 17333338, 27443514, 27720647, 19781682, 28779002, 23555315, 33095795) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 22, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 11, 2019	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 10, 2015	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2023	Variant summary: ATM c.334G>A (p.Ala112Thr) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 250408 control chromosomes (gnomAD, Hirsch_2008), predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant has also been found in 13/2559 (carrier freq=0.00508) African American women over the age of 70 without history of cancer (FLOSSIES dataset). c.334G>A has been reported in the literature in individuals affected with Breast Cancer, Lynch Syndrome, endometrial carcinoma, cerebellar ataxia, primary ovarian insufficiency and PDAC (examples: Tung_2014, Yurgelun_2015, Ring_2016, Coutelier_2018, Mullins_2019, Weitzel_2019, Franca_2020, Zimmermann_2021), but it was also reported in healthy controls (examples: Hirsch_2008, Weitzel_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, three as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

Ataxia-telangiectasia syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

- -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

The ATM c.334G>A variant is predicted to result in the amino acid substitution p.Ala112Thr. This variant has been reported in two individuals with breast cancer (Tung et al. 2014. PubMed ID: 25186627; Mullins and Gupta. 2019. PubMed ID: 31719806), in an individual with endometrial cancer (Ring et al. 2016. PubMed ID: 27443514, Table S2), an individual with primary ovarian insufficiency (França et al. 2020. PubMed ID: 33095795), and in at least two individuals undergoing Lynch syndrome genetic testing (Yorczyk et al. 2014. PubMed ID: 25318351, Table 2; Yurgelun et al. 2015. PubMed ID: 25980754, Table S2). It has also been reported in controls from breast cancer cohort studies (Hirsch et al. 2007. PubMed ID: 17333338; Tavtigian et al. 2009. PubMed ID: 19781682. Table S2). This variant is reported in 0.27% of alleles in individuals of African descent in gnomAD, which is significantly more common than other known disease-causing ATM variants. In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127370/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ATM p.Ala112Thr variant was identified in 4 of 17948 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer or Lynch syndrome and was present in 2 of 4988 control chromosomes (frequency: 0.0004) from healthy individuals (Haiman 2013, Hirsch 2008, Ring 2016, Tavtigian 2009, Yorczyk 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs146382972) as "With other allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by GeneDx and five other submitters), and MutDB. The variant was not identified in COGR, Cosmic, or LOVD 3.0 databases. The variant was identified in control databases in 74 of 276196 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 66 of 23976 chromosomes (freq: 0.003), Other in 1 of 6434 chromosomes (freq: 0.0002), and Latino in 7 of 34316 chromosomes (freq: 0.0002), while the variant was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala112 residue is 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) 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. -

Familial cancer of breast

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Apr 18, 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]. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.063

.;T;.;T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D;.;D

M_CAP

Benign

0.069

MetaRNN

Benign

0.016

T;T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.9

.;L;.;L;.

MutationTaster

Benign

0.56

N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

N;N;.;N;.

REVEL

Benign

0.11

Sift

Uncertain

0.011

D;D;.;D;.

Sift4G

Uncertain

0.019

D;D;D;D;D

Polyphen

0.87

.;P;.;P;.

Vest4

0.13, 0.060, 0.18

MVP

0.91

MPC

0.27

ClinPred

0.033

GERP RS

4.7

Varity_R

0.21

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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