11-108244065-C-T

Position:

• chr11-108244065-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000051.4(ATM):​c.609C>T​(p.Asp203=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,592 control chromosomes in the GnomAD database, including 3 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 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:20
• Conservation: PhyloP100: 2.03

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 11-108244065-C-T is Benign according to our data. Variant chr11-108244065-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135764.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Benign=8, Uncertain_significance=1}. Variant chr11-108244065-C-T is described in Lovd as [Likely_benign]. Variant chr11-108244065-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00164 (249/152030) while in subpopulation NFE AF= 0.00253 (172/67994). AF 95% confidence interval is 0.00222. There are 1 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.609C>T	p.Asp203=	synonymous_variant	6/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.609C>T	p.Asp203=	synonymous_variant	6/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 151914 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00147 AC: 368 AN: 251168 Hom.: 0 AF XY: 0.00152 AC XY: 206 AN XY: 135766

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00193 AC: 2823 AN: 1461562 Hom.: 2 Cov.: 34 AF XY: 0.00196 AC XY: 1425 AN XY: 727078

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00164 AC: 249 AN: 152030 Hom.: 1 Cov.: 32 AF XY: 0.00159 AC XY: 118 AN XY: 74300

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00114

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00138

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:20

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Asp203= variant was not identified in the literature nor was it identified in COGR, MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in dbSNP (ID: rs144709948) as “With other allele”, in ClinVar (4x as likely benign by Ambry Genetics, PreventionGenetics, and the University Midical Center Groningen and 3x as benign by Invitae, GeneDx, and Color Genomics). The variant was also listed the Cosmic database (1x in Acute myeloid leukemia). The variant was identified in control databases in 397 of 276884 chromosomes at a frequency of 0.001 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 12 of 24010 chromosomes (freq: 0.0005), Other in 15 of 6446 chromosomes (freq: 0.002), Latino in 33 of 34358 chromosomes (freq: 0.001), European Non-Finnish in 286 of 126536 chromosomes (freq: 0.002), Ashkenazi Jewish in 5 of 10148 chromosomes (freq: 0.0005), European Finnish in 36 of 25754 chromosomes (freq: 0.001), and South Asian in 10 of 30778 chromosomes (freq: 0.0003) while the variant was not observed in the East Asian, populations. The p.Asp203= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATM: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 10, 2019	- -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 27, 2014	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.609C>T p.(Asp203=) variant has an allele frequency of 0.00238 (0.23%, 281/ 117988 alleles) in the Non-Finnish European population of the gnomAD v2.1.1 non-cancer dataset (BS1; http://gnomad.broadinstitute.org). It is a silent variant not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer (BP4). The variant is located at a nucleotide that is not highly conserved across species, based on PhyloP (BP7). Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BP4 + BP7 (PMID: 33280026). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 20, 2021	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2014	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. -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 22, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

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

Apr 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.8
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs144709948; hg19: chr11-108114792; COSMIC: COSV53765648;