11-108325532-C-T

Position:

• chr11-108325532-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_000051.4(ATM):​c.6795C>T​(p.Phe2265Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,601,862 control chromosomes in the GnomAD database, including 1 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 0.00041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 0.258

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATM (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-108325532-C-T is Benign according to our data. Variant chr11-108325532-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135774.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=12, Uncertain_significance=1, Benign=2}.
• BP7: Synonymous conserved (PhyloP=0.258 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.6795C>T	p.Phe2265Phe	synonymous_variant	46/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6795C>T	p.Phe2265Phe	synonymous_variant	46/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000182 AC: 45 AN: 247590 Hom.: 0 AF XY: 0.000157 AC XY: 21 AN XY: 134172

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000516

Gnomad NFE exome AF: 0.000346

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000523 AC: 758 AN: 1449648 Hom.: 1 Cov.: 32 AF XY: 0.000465 AC XY: 336 AN XY: 721980

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000895

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: 0.000632

Gnomad4 OTH exome AF: 0.000916

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.000255 AC XY: 19 AN XY: 74420

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.000276

EpiCase AF: 0.000654

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ATM: BP4, BP7 -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 18, 2018	Variant summary: ATM c.6795C>T alters a non-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 0.00021 in 273300 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.6795C>T, has been reported in the literature with limited information (Bernstein_2010, Pettitt_2001). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (3x) and uncertain signifncance (1x). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 14, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 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. -

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

Jul 09, 2021

- -

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.Phe2265= variant was identified in 11 of 30,384 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer and was present in 8 of 10,976 control chromosomes (frequency: 0.0007) from healthy individuals (Bernstein 2010, Decker 2017). The variant was identified in dbSNP (rs3218699) as “with uncertain significance, other allele” and ClinVar (classified as likely benign by Color, Ambry Genetics, Invitae and 3 other submitters, benign by GeneDx and uncertain significance by Illumina). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 57 of 278,902 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 49 of 128,014 chromosomes (freq: 0.0004), Other in 2 of 7164 chromosomes (freq: 0.0003), Latino in 3 of 35,362 chromosomes (freq: 0.00009), African in 2 of 24,802 chromosomes (freq: 0.00008), Finnish in 1 of 22,828 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Phe2265= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and 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. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jun 10, 2024

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.69

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: rs3218699; hg19: chr11-108196259; COSMIC: COSV53782191; COSMIC: COSV53782191;