11-108253901-T-C

Position:

• chr11-108253901-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000051.4(ATM):​c.1986T>C​(p.Phe662=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,613,978 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 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (0 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:25
• Conservation: PhyloP100: 2.87

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-108253901-T-C is Benign according to our data. Variant chr11-108253901-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135740.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Benign=7, Uncertain_significance=1}. Variant chr11-108253901-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.87 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.1986T>C	p.Phe662=	synonymous_variant	13/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1986T>C	p.Phe662=	synonymous_variant	13/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000477 AC: 120 AN: 251376 Hom.: 0 AF XY: 0.000464 AC XY: 63 AN XY: 135854

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000827

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000642 AC: 939 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.000639 AC XY: 465 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000762

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74366

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000749 Hom.: 0

Bravo AF: 0.000484

EpiCase AF: 0.000818

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:25

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ATM: BP4, BS1:Supporting -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 09, 2023	- -

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2019	Variant summary: ATM c.1986T>C alters a conserved nucleotide resulting in a synonymous change. 5/5 computational 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 0.00048 in 277242 control chromosomes, predominantly at a frequency of 0.0011 within the Ashkenazi Jewish subpopulation and at a frequency of 0.00083 in the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish and Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism. c.1986T>C has been reported in the literature in individuals affected with cancer, including breast cancer, non-Hodgkin lymphoma and chronic lymphocytic leukemia (Skowronska_2012, Bernstein_2010, Sipahimalani_2007, Vorechovsky_1996). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported in our internal database (PALB2 c.761C>G, p.Ser254X; BRCA1 c.68_69delAG, p.E23fs*17), providing supporting evidence for a benign role. Additionally, the variant was detected in heterozygous state in 12 control individuals in the FLOSSIES database (individuals aged over 70 who never had cancer), providing further supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 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. -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 07, 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, criteria provided, single submitter	curation	Sema4, Sema4	May 04, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 14, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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	Counsyl	Mar 29, 2018	- -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 02, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

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

Aug 16, 2019

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Phe662= variant was identified in 2 of 348 proband chromosomes (frequency: 0.006) from Swedish and Canadian individuals or families with breast cancer (and a family history of tumours associated with AT) and non-Hodgkin lymphoma, and was not identified in 126 control chromosomes from healthy individuals (Vorechovsky_1996_ 8797579, Sipahimalani_2007_17640065). The variant was also found in 2 cell lines derived from non-lymphoid malignancies (Ejima_2000_ 10738255). The variant was identified in dbSNP (ID: rs1800055) “With Likely benign allele”, ClinVar (classified benign by GeneDx, and likely benign by Invitae, Ambry Genetics, Color Genomics Inc and ARUP), Clinvitae (3x), and was not identified in Cosmic, MutDB, LOVD 3.0, or ATM-LOVD. The variant was also identified in control databases in 133 of 277116 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observation by population include: African in 2 of 24036 chromosomes (freq: 0.00008), “Other” in 3 of 6460 chromosomes (freq: 0.0005), Latino in 10 of 34418 chromosomes (freq: 0.0003), European Non-Finnish in 105 of 126626 chromosomes (freq: 0.0008), Ashkenazi Jewish in 11 of 10148 chromosomes (freq: 0.001), and European Finnish in 2 of 25782 chromosomes (freq: 0.00008); it was not observed in the East Asian and South Asian populations. The p.Phe662= 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. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Feb 19, 2024

According to the ClinGen ACMG ATM v1.1.0 criteria we chose these criteria: BP7 (supporting benign): A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice Own RNA-Analysis revealed no effect on splicing, BS1 (strong benign): Filtering Allele Frequency >.05% (0.0006509) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1800055; hg19: chr11-108124628;