rs730881389

Positions:

chr11-108284328-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000051.4(ATM):c.3848T>C(p.Leu1283Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.39

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 11-108284328-T-C is Pathogenic according to our data. Variant chr11-108284328-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108284328-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.3848T>C	p.Leu1283Pro	missense_variant	26/63	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.3848T>C	p.Leu1283Pro	missense_variant	26/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727168

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 14, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 08, 2023	_x000D_ Criteria applied: PS4, PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 12, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 23, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12072877, 12552559, 21833744]. Functional studies indicate this variant impacts protein function [PMID: 12072877]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 14, 2023	The p.L1283P variant (also known as c.3848T>C), located in coding exon 25 of the ATM gene, results from a T to C substitution at nucleotide position 3848. The leucine at codon 1283 is replaced by proline, an amino acid with similar properties. This alteration has been observed with at least three different pathogenic ATM mutations in a compound heterozygous state in multiple individuals diagnosed with ataxia telangiectasia (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sun X et al. J. Pediatr. 2002 Jun;140:724-31; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31; Soukupova J et al. Neuromolecular Med. 2011 Sep;13:204-11; Pietrucha B et al. J. Pediatr. Hematol. Oncol. 2010 Jan;32(1):e28-30; personal communication; Miasaki FY et al. J Endocr Soc, 2022 Apr;6:bvac026). This alteration has also been identified in individuals diagnosed with breast cancer (Lu HM et al. JAMA Oncol, 2019 01;5:51-57). Additionally, this variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Based on internal structural assessment, this alteration results in structural destabilization of one of the HEAT repeat coils (Ambry internal data; Tsai WW et al. Nature. 2010 Dec;468:927-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 17, 2024	This missense variant replaces leucine with proline at codon 1283 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant, however, neither ATM protein nor TP53 kinase activity was detectable in cells from ataxia-telangiectasia patients harboring this variant (PMID: 12072877). This variant has been reported in individuals affected with breast cancer (PMID: 30128536) and observed to co-occur with multiple distinct pathogenic ATM variants in patients diagnosed with ataxia-telangiectasia (PMID: 12072877, 12552559, 20051774, 21833744). In a large international case-control study, this variant was reported in 1/60465 breast cancer cases and 1/53460 controls (OR=0.884, 95%CI 0.055 to 14.136, p-value=1; PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Ataxia-telangiectasia syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1283 of the ATM protein (p.Leu1283Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia, pancreatic cancer and breast and/or ovarian cancer (PMID: 12072877, 21833744, 30128536, 31341520, 35047863, 35284771). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 181994). 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 disruptive. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2024

Published functional studies support a damaging effect: lymphoblastoid cell line from an ataxia-telangiectasia patient showed no detectable ATM protein and absent kinase activity (PMID: 12072877); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24568663, 28126470, 10330348, 21833744, 12552559, 20051774, 21164480, 37075885, 35585550, 35047863, 35284771, 12072877) -

Malignant tumor of breast

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 27, 2021

Variant summary: ATM c.3848T>C (p.Leu1283Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 260692 control chromosomes (gnomAD and publication data). c.3848T>C has been reported in the literature in individuals affected with breast cancer and ovarian cancer (Lu_2019, Arvai_2019). Additionally, this variant has been observed with other pathogenic variants in individuals affected with ataxia-telangiectasia (Sun_2002, Pietrucha_2010, Soukupova_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

.;D;D

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;D;.

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.9

.;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.2

D;D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.98, 0.99

MutPred

0.93

Loss of stability (P = 0.019);Loss of stability (P = 0.019);Loss of stability (P = 0.019);

MVP

0.97

MPC

0.74

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.85

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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