11-108329066-C-G

Position:

chr11-108329066-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000051.4(ATM):c.7135C>G(p.Leu2379Val) 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 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 0.258

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:

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.7135C>G	p.Leu2379Val	missense_variant	49/63	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.7135C>G	p.Leu2379Val	missense_variant	49/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251424

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

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:

0.0000123

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000358

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 14, 2022	The ATM c.7135C>G (p.Leu2379Val) missense change has a maximum frequency of 0.038% in gnomAD v2.1.1. Algorithms that predict the impact of sequence changes on splicing indicate that this variant may create a novel splice donor site. RNA studies demonstrate that this variant leads to partial skipping of exon 49 due to the activation of a cryptic splice donor site (PMID: 33011440, internal data), and subsequently leads to out of frame alternative splicing that is expected to produce a truncated protein. This variant has been reported in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 33011440). Case-control studies are not available to determine the prevalence of the variant in affected individuals compared with the prevalence in controls. This variant currently meets the criteria to be classified as of uncertain significance based on the ClinGen hereditary breast, ovarian and pancreatic cancer expert panel specifications to the ACMG/AMP variant interpretation guidelines for ATM. However, additional evidence in the future may allow for re-classification of this variant as likely pathogenic. In summary, the available evidence is currently insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2379 of the ATM protein (p.Leu2379Val). This variant is present in population databases (rs778888033, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant has been observed to co-occur in individuals with a different variant in ATM gene that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 186475). 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. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression. However, the splicing effect is incomplete and of unknown impact (PMID: 33011440; Invitae) 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:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 14, 2022	This missense variant replaces leucine with valine at codon 2379 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). Splice site prediction tools suggest that this variant may create a splice donor site. A study using RNA from carrier-derived lymphocytes has shown that this variant leads to partial use of this donor site, resulting in the deletion of the last 173 nucleotides of exon 49 in the RNA transcript (PMID: 33011440). The aberrant transcript is expected to create a premature translation stop signal and result in an absent or non-functional protein product. An incomplete splice defect resulting from this variant has also been reported in ClinVar (ClinVar variation ID: 186475). This variant has been reported in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 33011440) and in an individual affected with multiple myeloma (PMID: 29954938). This variant has also been identified in 13/251424 chromosomes (13/34584 Latino 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	Nov 15, 2023	The p.L2379V variant (also known as c.7135C>G), located in coding exon 48 of the ATM gene, results from a C to G substitution at nucleotide position 7135. The leucine at codon 2379 is replaced by valine, an amino acid with highly similar properties. This variant was reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has been reported in individuals with personal and/or family history of breast cancer (Feliubadaló L et al. Clin Chem, 2021 03;67:518-533). RNA analysis from carrier-derived lymphocytes has shown that this variant leads to a partial skipping of 173nt at the 3' end of exon 49 resulting in a truncated protein, however, they also observed approximately 10% of full-length transcripts also carrying this variant (Rofes P et al. J Mol Diagn, 2020 12;22:1453-1468). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Internal RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.7135C>G variant has an allele frequency of 0.0055%, (13/236,890 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.038%, (13/34,252 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It does not lead to a splicing alteration as per SPiCE predictor, but a new donor site is created/activated, with a score exceeding the one of the natural site, according to 3 splicing predictors of the set SpliceSiteFinderlike-MaxEntScan-NNSplice-GeneSplicer (PP3). RNA analysis studies in a breast cancer patient RNA revealed a partial skipping at the 3’ end of exon 49. A Single-nucleotide primer extension (SNuPE) assay showed that the alteration is not complete, but the variant allele produces more than 90% of altered transcript, r.[7135c>g,7135_7307del]. The altered transcript is expected to produce a frame-shift with a premature STOP codon and nonsense-mediated decay, p.[Leu2379Val,Leu2379Ilefs*13] (PS3_Moderate, PMID: 33011440). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PP3 + PS3_Moderate (PMID: 33280026). -

Familial cancer of breast

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Apr 09, 2020	To our knowledge, this variant has not been reported in the literature. This variant has an overall allele frequency of 0.00005 in the Broad Institute gnomAD Browser, and was found only in individuals of Latino ancestry (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant may not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 13, 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 provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2024	Identified in individuals with personal or family history of breast and/or other cancers (PMID: 33011440, 38049230); Published RNA studies demonstrate aberrant splicing resulting in partial skipping of exon 49 identified in the majority of transcripts and less than 10% full-length transcript (PMID: 33011440); In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 29954938, 30761385, 33280026, 33471991, 33011440, 38049230, 23532176) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	ATM: PS3:Moderate, PP3 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 22, 2024

Variant summary: ATM c.7135C>G (p.Leu2379Val) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic exonic 5' splice donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in partial skipping of 173 nucleotides at 3' end of exon 49 which is predicted to result in a protein truncation (Rofes_2020). However, this study was performed on leukocyte derived RNA, therefore, the exact in-vivo implications of this finding are uncertain and the authors proposed a VUS classification. The variant allele was found at a frequency of 5.2e-05 in 251424 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.7135C>G has been reported in the literature in settings of multiple myeloma, a personal and/or family history of breast or ovarian cancer as well as at-least one healthy 44 year old unaffected individual with a maternal history of ovarian cancer (e.g. Ruiz-Heredia_2018, Rofes_2020, Feliubadal_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 33280026, 33011440, 29954938). ClinVar contains an entry for this variant (Variation ID: 186475). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.068

T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.77

T;.

M_CAP

Benign

0.069

MetaRNN

Benign

0.39

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.42

N;N

REVEL

Benign

0.17

Sift

Uncertain

0.016

D;D

Sift4G

Benign

0.21

T;T

Polyphen

0.95

P;P

Vest4

0.46

MutPred

0.66

Loss of stability (P = 0.059);Loss of stability (P = 0.059);

MVP

0.86

MPC

0.17

ClinPred

0.22

GERP RS

3.8

Varity_R

0.17

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.81

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.81

Position offset: -1

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