11-108329118-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000051.4(ATM):c.7187C>G(p.Thr2396Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. T2396T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:7 O:1
• Conservation: PhyloP100: 1.67

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12823218).
• BP6: Variant 11-108329118-C-G is Benign according to our data. Variant chr11-108329118-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127438.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=9, not_provided=1, Benign=2}. Variant chr11-108329118-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7187C>G	p.Thr2396Ser	missense_variant	49/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7187C>G	p.Thr2396Ser	missense_variant	49/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251332 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000360 AC: 526 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.000359 AC XY: 261 AN XY: 727188

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000537

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: 0.000435

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74316

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ATM: PM2, BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 31, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 08, 2023	BP4 -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 07-22-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9288106, 19781682, 29036293, 11054065, 25980754, 22529920, 19404735, 18384426, 21787400, 20826828, 10026998, 26787654, 28779002, 27443514, 20305132, 25186627, 28135145, 31159747, 29522266) -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 14, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 01, 2021	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Apr 09, 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. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2021	Variant summary: ATM c.7187C>G (p.Thr2396Ser) results in a conservative amino acid change located in the FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 256616 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00021 vs 0.001), allowing no conclusion about variant significance. In addition, the variant was also reported in 3/7325 European American women (i.e. with a frequency of 0.00041), who were older than 70 years of age, and never had cancer (in the FLOSSIES database). c.7187C>G has been reported in the literature as a VUS in settings of multigene cancer panel testing in individuals affected with a variety of cancers (example, breast, ovarian, melanoma, CLL, Lynch syndrome) with limited information (e.g. Paglia 2010, Tung_2015, Tavera-Tapia 2017, Goldstein 2017, Tiao 2017, Hauke 2018, Bonache_2018, Tsaousis_2019, Ferrer-Avargues_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature as we all as observed at our laboratory (our lab, BRCA1 c.3400G>T, p.Glu1134* ; Ferrer-Avargues_2021, MSH6 c.2079dup, p.Cys694MetfsTer), providing supporting evidence for a benign role. To our knowledge, no concrete experimental evidence demonstrating an impact on protein function has been reported. Ten 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=1; likely benign, n=2, VUS, n=7). At-least one of these submitters has re-classified this variant to likely benign since its previous evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 21, 2022

- -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Oct 23, 2023

The ATM c.7187C>G (p.Thr2396Ser) missense change has a maximum subpopulation frequency of 0.045% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer and/or ovarian cancer (PMID: 18384426, 19404735, 25186627, 30306255, 31159747). This variant has been reported in 3 individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/) and in 4 of 1358 control individuals collected as part of a non-cancer studies (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.047	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.66	T;.
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.050
Sift	Benign	0.27	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.095	B;B
Vest4		0.32
MutPred		0.30		Gain of disorder (P = 0.0207);Gain of disorder (P = 0.0207);
MVP		0.80
MPC		0.12
ClinPred		0.029	T
GERP RS		3.8
Varity_R		0.15
gMVP		0.064

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: rs370559102; hg19: chr11-108199845; COSMIC: COSV53755657; COSMIC: COSV53755657;