chr11-108235838-T-C

Variant names:

• chr11-108235838-T-C
• rs587781375
• NM_000051.4:c.496+4T>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000051.4(ATM):​c.496+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002151
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:12
• Conservation: PhyloP100: -0.392

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16636845).
• BP6: Variant 11-108235838-T-C is Benign according to our data. Variant chr11-108235838-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140926.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=1, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.496+4T>C		splice_region_variant, intron_variant	Intron 5 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.496+4T>C		splice_region_variant, intron_variant	Intron 5 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251312 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135822

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: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000787 AC: 115 AN: 1461444 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727046

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: 0.000101

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74492

Gnomad4 AFR AF: 0.0000241

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:5

Jul 13, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 18, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2017

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 16, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 17, 2020

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The intronic c.496+4T>C variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer (BP4). Splicing analysis in carrier RNA with proper design and controls showed only the wild-type transcript although do not demonstrate biallelic expression by an exonic SNV (BS3_Supporting; O.Díez, unpublished data). This variant has an allele frequency of 0.000082 (0.008%, 22/268,180 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00019 (0.02%, 22/118,056 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BP4 + BS3_Supporting (PMID: 33280026). -

Feb 05, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Uncertain:2 Benign:1

Feb 05, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.496+4T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation 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 8.8e-05 in 251312 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (8.8e-05 vs 0.001), allowing no conclusion about variant significance. c.496+4T>C has been reported in the literature in individuals affected with Breast Cancer (Jalkh_2017, Mitchell_2018), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with disease. The variant was also reported in 2/7325 European American women, who were older than age 70, and have never had cancer (FLOSSIES database). 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: 28202063, 29659587, 25980754). ClinVar contains an entry for this variant (Variation ID: 140926). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Nov 21, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ataxia-telangiectasia syndrome Uncertain:2 Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:1 Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BP4, BS1 -

Sep 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 28202063 (2017), 28779002 (2017), 29659587 (2018)) and colorectal cancer (PMID: 33280026 (2021)). Additionally, this variant has been observed in elderly cancer free women (Flossies, (https://whi.color.com/)). The frequency of this variant in the general population, 0.00018 (23/129072 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect ATM mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. -

ATM-related disorder Benign:1

Jul 31, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.496+4T>C variant was identified in 4 of 2610 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and Lynch Syndrome (Jalkh 2017,Yurgelun 2015, ). The variant was identified in dbSNP (rs587781375) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Counsyl, Integrated Genetics and 4 other submitters, benign by GeneDx and likely benign by Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 23 of 282,719 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 23 of 129,072 chromosomes (freq: 0.0002), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The variant was reported in an individual with a co-occurring pathogenic STK11 variant (c.375-1C>T) (Jalkh 2017). The c.496+4T>C variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 4 out of 4 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary cancer Benign:1

Feb 27, 2025

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Familial cancer of breast Benign:1

Apr 19, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. 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]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.46
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.17	T
Sift4G	Uncertain	0.012	D
Vest4		0.22
MVP		0.90
GERP RS		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs587781375; hg19: chr11-108106565; COSMIC: COSV53770952; COSMIC: COSV53770952;