11-108250981-G-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS1

The NM_000051.4(ATM):c.1516G>T(p.Gly506Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000459 in 1,613,942 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:3

Conservation

PhyloP100: 6.40

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3080017).

BP6

Variant 11-108250981-G-T is Benign according to our data. Variant chr11-108250981-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127339.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000472 (69/1461832) while in subpopulation MID AF= 0.00537 (31/5768). AF 95% confidence interval is 0.00389. There are 1 homozygotes in gnomad4_exome. There are 35 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.1516G>T	p.Gly506Cys	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.1516G>T	p.Gly506Cys	missense_variant	Exon 10 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152110

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:

0.0000398

AC:

AN:

251234

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135798

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:

0.0000704

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74308

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:

0.0000329

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Dec 17, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with cysteine at codon 506 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 with bilateral breast cancer (PMID: 34299313). In a large international case-control study, this variant was reported in 8/60458 breast cancer cases and 4/53457 controls (OR=1.768, 95%CI 0.532 to 5.873, p-value=0.399; PMID: 33471991). A report by Algahtani et al, 2021 (PMID: 32172615) identified this variant in the homozygous state in a Saudi female with onset of atypical ataxia-telangiectasia at 14 years old. This individual had slow disease progression with neurodegenerative symptoms but no immune system deficiencies and normal endocrine function. Her sister was also homozygous for this variant and exhibited similar atypical ataxia-telangiectasia symptoms with disease onset at 16 years old. Their parents were first degree cousin, had no symptoms, and were heterozygous for this variant. The proband had 8 unaffected siblings, one of whom was genotyped and shown to be heterozygous for this variant. This variant has also been identified in 11/282626 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. -

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G506C variant (also known as c.1516G>T), located in coding exon 9 of the ATM gene, results from a G to T substitution at nucleotide position 1516. The glycine at codon 506 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported as homozygous in a Saudi female with onset of ataxia telangiectasia (A-T) at age 14 with classic neurodegenerative symptoms clinically and on imaging but without immune system dysfunction or endocrine abnormalities. Another affected sister was also homozygous for this alteration, while three heterozygous family members did not have features of A-T (Algahtani H et al. Int J Neurosci, 2020 Mar;:1-6). This variant has also been identified in individuals with breast cancer and in one proband with cutaneous melanoma (Decker B et al. J Med Genet, 2017;54:732-741; Hauke J et al. Cancer Medicine, 2018;7(4):1349-1358; Pastorino L et al. Cancers, 2020 04;12(4):1007; Guglielmi C et al. Int J Mol Sci, 2021 Jul;22). This alteration was seen in a total of 11/61,198 breast cancer cases as well as 6/53,951 controls across two studies (Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Dorling et al. N Engl J Med. 2021 02;384:428-439). In another study, this alteration was reported in the germline of 5 of 8,920 ethnically matched normal population control subjects but was not seen in 516 samples from a study of chronic lymphocytic leukemia patients of European descent (Tiao G et al. Leukemia, 2017 10;31:2244-2247). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ataxia-telangiectasia syndrome

Uncertain:2Benign:1

May 02, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2Benign:1

Apr 28, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25318351, 27997549, 26786923, 32172615, 24123366, 28652578, 32325837) -

Dec 06, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:1

Aug 23, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.1516G>T (p.Gly506Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00004585 in 1613942 control chromosomes, predominantly at a frequency of 0.005095 within the Middle Eastern subpopulation in the gnomAD v4 database, including one homozygote. The observed variant frequency within Middle Eastern control individuals in the gnomAD database is approximately 1.25 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Middle Eastern origin. c.1516G>T has been reported in the literature in individuals affected with different types of cancer (Algahtani_2020, Pastorino_2020, Dalmasso_2021, de Oliveira_2022, AlHarbi_2023, Lima_2023). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.5251C>T, p.Arg1751*; MSH2 c.862C>T, p.Gln288*), providing supporting evidence for a benign role (AlHarbi_2023). 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: 37306523, 32172615, 34262154, 37529773, 32325837, 35534704). ClinVar contains an entry for this variant (Variation ID: 127339). Based on the evidence outlined above, the variant was classified as likely benign. -

Jun 11, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.1516G>T, in exon 10 that results in an amino acid change, p.Gly506Cys. This sequence change does not appear to have been previously described in patients with ATM-related disorders and has been described in the gnomAD database with a frequency of 0.007% in the European sub-population (dbSNP rs587779816). The p.Gly506Cys change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. The p.Gly506Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly506Cys change remains unknown at this time. -

Breast and/or ovarian cancer

Uncertain:1

Oct 05, 2021

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

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related disorder

Uncertain:1

Jul 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.1516G>T variant is predicted to result in the amino acid substitution p.Gly506Cys. This variant has been reported in the homozygous state in two siblings with ataxia telangiectasia (Algahtani et al. 2021. PubMed ID: 32172615). This variant has been reported in patients with colorectal, breast or ovarian cancer, and melanoma (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; File S2, Howitt et al. 2014. PubMed ID: 25231023; Cock-Rada et al. 2018. PubMed ID: 28528518, Pastorino et al. 2020. PubMed ID: 32325837), but was also reported in three healthy control individuals in a study of patients with chronic lymphocytic leukemia (Table S6, Tiao et al. 2017. PubMed ID: 28652578). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108121708-G-T) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127339/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Jun 06, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

a variant of uncertain significance in the ATM gene (p.Gly506Cys). This sequence change replaces glycine with cysteine at codon 506 of the ATM protein (p.Gly506Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant has been reported in the literature in individuals with ATM-related disease (PMID 32172615, 32325837). ClinVar contains an entry for this variant (Variation ID: 127339) with 6 submissions: 1 likely benign and 5 uncertain significance, conflicting interpretations. In-silico predictions for this varint show Pathogenic computational verdict based on 7 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster and SIFT vs 5 benign predictions from BayesDel_addAF, DEOGEN2, LIST-S2, MVP and PrimateAI. for these reasons, this variant has been classified as a Variant of Uncertain Significance. Pathogenic mutations in the ATM gene cause autosomal dominant Susceptibility to Breast Cancer (OMIM 114480). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.0041

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.098

.;T;T

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;T;.

M_CAP

Benign

0.054

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.6

.;M;M

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

N;N;N

REVEL

Benign

0.28

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.94

.;P;P

Vest4

0.64, 0.59

MVP

0.90

MPC

0.40

ClinPred

0.32

GERP RS

6.2

Varity_R

0.45

gMVP

0.26

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