11-108249096-T-C

Position:

• chr11-108249096-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):​c.1229T>C​(p.Val410Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00282 in 1,613,936 control chromosomes in the GnomAD database, including 11 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 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:26 O:1
• Conservation: PhyloP100: 7.12

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012444019).
• BP6: Variant 11-108249096-T-C is Benign according to our data. Variant chr11-108249096-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127332.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=13, Uncertain_significance=3, not_provided=1, Benign=8}. Variant chr11-108249096-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00185 (281/152280) while in subpopulation AMR AF= 0.00392 (60/15290). AF 95% confidence interval is 0.00313. There are 2 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.1229T>C	p.Val410Ala	missense_variant	9/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1229T>C	p.Val410Ala	missense_variant	9/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 152162 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00222 AC: 558 AN: 251102 Hom.: 2 AF XY: 0.00229 AC XY: 311 AN XY: 135716

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00292 AC: 4273 AN: 1461656 Hom.: 9 Cov.: 33 AF XY: 0.00278 AC XY: 2021 AN XY: 727132

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.00291

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00346

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00185 AC: 281 AN: 152280 Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74452

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00328 Hom.: 2

Bravo AF: 0.00230

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00216 AC: 262

EpiCase AF: 0.00278

EpiControl AF: 0.00373

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:26 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:6

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 11, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2016	Variant summary: The ATM c.1229T>C (p.Val410Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 270/126714 control chromosomes (2 homozygotes) at a frequency of 0.0021308, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0005001), suggesting this variant is likely a benign polymorphism. This variant has been found in patients with various types of cancer, including breast cancer, uterine serous carcinoma, lymphoma, chronic lymphocytic leukemia, and melanoma. It has not been reported in patients with ataxia-telangiectasia. Two large case-control studies showed that this variant is not associated with breast cancer (Tavtigian 2009; Haiman 2013). Thus available patient and control data show that this variant is a polymorphism found in patients as well as unaffected individuals. In addition, three clinical laboratories have classified this variant as benign/likely benign albeit another lab consider it as uncertain significance, all without evidence to independently evaluate. Taken together, this variant has been classified as Likely benign until more evidence becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ATM: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 21, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 13, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 22, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 14, 2017	- -

Ataxia-telangiectasia syndrome Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:5 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2015	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 12, 2023

- -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Val410Ala variant was identified in 5 of 1492 proband chromosomes (frequency: 0.003) from Dutch and Austrian individuals or families with breast cancer or ovarian cancer, and individuals with pediatric ALL (acute lymphocytic leukemia), and was identified in 2 of 644 chromosomes (frequency: 0.003) from healthy individuals (Broeks_2008_17393301, Thorstenson_2003_12810666, Liberzon_2004_14695997). The variant was also identified as a somatic mutation in 2 studies screening CRCs and lymphomas (Dallol_2016_ 27146902, Fang_2003_12149228). The variant was identified in dbSNP (ID: rs56128736) “With other allele”, ClinVar (wth conflicting interpretations of pathogenicity; submitters: benign by Ambry Genetics, GeneDx, and Invitae, likely benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), uncertain significance by Vantari Genetics and Genetic Services Laboratory (University of Chicago), and classification not provided by ITMI), Clinvitae (4x), Cosmic (7x in malignant melanoma, lymphoid neoplasm and carcinoma of the lung), LOVD 3.0, and in control databases in 582 (3 homozygous) of 276862 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 18 of 24018 chromosomes (freq: 0.0007), Other in 14 of 6458 chromosomes (freq: 0.002), Latino in 105 of 34390 chromosomes (freq: 0.003), European Non-Finnish in 401 (2 homozygous) of 126452 chromosomes (freq: 0.003), Ashkenazi Jewish in 41 (1 homozygous) of 10138 chromosomes (freq: 0.004), European Finnish in 3 of 25762 chromosomes (freq: 0.0001), while not observed in the East Asian and South Asian populations. The variant was not identified in GeneInsight-COGR or MutDB. The p.Val410 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Ala to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

ATM-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

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). -

Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Apr 25, 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]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	.;T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.43	.;B;B
Vest4		0.42, 0.47
MVP		0.99
MPC		0.23
ClinPred		0.065	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.48

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

Other links and lift over

dbSNP: rs56128736; hg19: chr11-108119823; COSMIC: COSV53726818; COSMIC: COSV53726818;