11-108268575-C-G

Position:

chr11-108268575-C-G

Variant summary

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

The NM_000051.4(ATM):c.2804C>G(p.Thr935Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. T935M) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.930

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:

ATM (HGNC:):

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=0.030701786).

BP6

Variant 11-108268575-C-G is Benign according to our data. Variant chr11-108268575-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185083.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}. Variant chr11-108268575-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000787 (115/1461724) while in subpopulation EAS AF= 0.00287 (114/39660). AF 95% confidence interval is 0.00245. There are 0 homozygotes in gnomad4_exome. There are 51 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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.2804C>G	p.Thr935Arg	missense_variant	18/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.2804C>G	p.Thr935Arg	missense_variant	18/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152140

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:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251396

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

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:

0.0000787

AC:

115

AN:

1461724

Hom.:

Cov.:

AF XY:

0.0000701

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:

0.00287

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 935 of the ATM protein (p.Thr935Arg). This variant is present in population databases (rs3218708, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, biliary tract cancer, uterus cancer (PMID: 25625042, 34326862, 36243179). ClinVar contains an entry for this variant (Variation ID: 185083). 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 cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2023	The p.T935R variant (also known as c.2804C>G), located in coding exon 17 of the ATM gene, results from a C to G substitution at nucleotide position 2804. The threonine at codon 935 is replaced by arginine, an amino acid with similar properties. This variant has been detected in a Brazilian individual with sporadic breast cancer and loss-of-heterozygosity observed in her tumor (Mangone FR et al. Springerplus. 2015 Jan;4:23). This alteration was identified in a cohort of patients diagnosed with biliary tract carcinoma undergoing multigene panel testing for hereditary cancer risk (Terashima T et al. Oncotarget. 2019 Oct;10:5949-5957). This alteration was observed in with an allele frequency of 0.00979 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.01005 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0091 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This variant has also been identified in 99/12403 unselected Japanese colorectal cancer patients and in 226/23478 controls (Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9). This amino acid position is poorly 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2022	This missense variant replaces threonine with arginine at codon 935 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 breast cancer (PMID: 25625042, 33471991). In a Japanese colorectal cancer risk case-control study, this variant was reported in 99/12502 colorectal cancer cases and 226/23704 controls (PMID: 33309985). This variant has been identified in 5/251396 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 provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or colorectal cancer as well as unaffected controls (Mangone et al., 2015; Momozawa et al., 2018; Fujita et al., 2020); This variant is associated with the following publications: (PMID: 25625042, 29642553, 33309985, 30287823, 31666926) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 13, 2023

Variant summary: ATM c.2804C>G (p.Thr935Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 298352 control chromosomes, predominantly at a frequency of 0.00027 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the gnomAD database are insufficient to allow any conclusion about variant significance. c.2804C>G has been reported in the literature predominantly in reports of East Asian/Japanese cohorts of unaffected controls and in ethnicity-matched individuals affected with breast/colorectal cancer and/or with a personal/family history of cancer (example, Jiang_2018, Mangone_2015, Fujita_2020, Terashima_2019, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. At least one recent report classifies this variant as benign based on a high frequency in Japanese population (Fujita_2020). It has also been reported at an allele frequency of 0.0061 in the Japanese Whole Genome Reference Panel (ToMMo 38KJPN) dataset of 38,000 Japanese individuals, including 7 homozygotes, strongly suggesting it is a benign polymorphism found primarily in individuals of East Asian/Japanese ancestry. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one Japanese research foundation have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=6) or likely benign (n=1). Some submitters cite overlapping but not all evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.36

DANN

Benign

0.61

DEOGEN2

Benign

0.086

.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.54

T;T;.

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.031

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.60

.;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.49

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0010

.;B;B

Vest4

0.18, 0.24

MVP

0.53

MPC

0.14

ClinPred

0.025

GERP RS

-1.3

Varity_R

0.036

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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