rs34231402

chr11-108257519-T-Achr11-108257519-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000051.4(ATM):c.2289T>A(p.Phe763Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,613,946 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F763F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:19
• Conservation: PhyloP100: 0.180

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012982547).
• BP6: Variant 11-108257519-T-A is Benign according to our data. Variant chr11-108257519-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127347.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=8, Benign=5}. Variant chr11-108257519-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000389 (569/1461590) while in subpopulation MID AF= 0.00383 (22/5746). AF 95% confidence interval is 0.00259. There are 1 homozygotes in gnomad4_exome. There are 281 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2289T>A	p.Phe763Leu	missense_variant	15/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2289T>A	p.Phe763Leu	missense_variant	15/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000906 AC: 138 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000700 AC: 176 AN: 251276 Hom.: 1 AF XY: 0.000641 AC XY: 87 AN XY: 135816

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000501

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000389 AC: 569 AN: 1461590 Hom.: 1 Cov.: 31 AF XY: 0.000386 AC XY: 281 AN XY: 727112

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.000899 AC XY: 67 AN XY: 74516

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000590 Hom.: 0

Bravo AF: 0.00131

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:19

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ATM: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 29, 2017	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 24, 2018	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 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 10, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Oct 27, 2021	- -

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 12, 2021	- -
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	Athena Diagnostics	Jul 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 18, 2021	Variant summary: ATM c.2289T>A (p.Phe763Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 252946 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of 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 found primarily in populations of African or African-American origin. The variant has been identified in numerous patients with HBOC or other types of cancer and control cohorts reported in the literature, without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with a pathogenic variant has been reported (SMAD4 c.1194G>A, p.W398Ter, Martin-Morales_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign n =4, likely benign n=5, VUS n=3). Based on the evidence outlined above, the variant was classified as benign. -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

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

Dec 23, 2022

- -

Familial ovarian cancer Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Phe763Leu variant was identified in 10 of 8114 proband chromosomes (frequency: 0.0012) from individuals or families with breast cancer, Hodgkin’s Disease and individuals testing for Lynch Syndrome; the variant was present in 7 of 5394 control chromosomes (frequency: 0.012) from healthy individuals (Sommer_2002_11996792, Offit_2002_12473594, Hirsch_2008_17333338, Paglia_2010_19404735, Tavtigian-2009_19781682, Yurgelun_2015_22529920). The variant was also identified in dbSNP (ID: rs34231402) as “With Uncertain significance allele”, ClinVar (2x as uncertain significance by GeneDx and Flugent Genetics, 1x as likely benign by Ambry Genetics, 1x as benign by Invitae), Clinvitae (3x as likely benign and uncertain significance) databases. The variant was not identified in Cosmic, MutDB and LOVD 3.0, databases. The variant was identified in control databases in 186 of 277044 chromosomes (1 homozygous) at a frequency of 0.0007 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 42 of 24034 chromosomes (freq: 0.0012), Other in 14 of 6462 chromosomes (freq: 0.002), Latino in 63 of 34418 chromosomes (freq: 0.002), European Non-Finnish in 54 of 126666 chromosomes (freq: 0.0004), Ashkenazi Jewish in 13 of 10152 chromosomes (freq: 0.0013), while the variant was not observed in the East Asian, European Finnish, and South Asian populations. The p.Phe763Leu residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	14
Dann	Benign	0.97
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.63	T;T;.
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.98	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.0030	.;B;B
Vest4		0.14, 0.19
MutPred		0.20		Loss of methylation at K764 (P = 0.0466);Loss of methylation at K764 (P = 0.0466);Loss of methylation at K764 (P = 0.0466);
MVP		0.88
MPC		0.14
ClinPred		0.015	T
GERP RS		5.0
Varity_R		0.046
gMVP		0.16

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: rs34231402; hg19: chr11-108128246;