11-108326225-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000051.4(ATM):c.6975G>C(p.Ala2325=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000316 in 1,613,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2325A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:12
• Conservation: PhyloP100: 4.81

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 Uncertain_significance. Variant got 4 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.6975G>C	p.Ala2325=	splice_region_variant, synonymous_variant	47/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.6975G>C	p.Ala2325=	splice_region_variant, synonymous_variant	47/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151776 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251310 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000351

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151776 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74098

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 19, 2022	The c.6975G>C variant (also known as p.A2325A) is located in coding exon 46 of the ATM gene. This variant results from a G to C substitution at nucleotide position 6975. This nucleotide substitution does not change the alanine at codon 2325. However, this change occurs in the last base pair of coding exon 46, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in 0/13087 breast cancer cases and 1/5488 control individuals in the UK (Decker B et al. J Med Genet. 2017 11;54:732-741). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2023	This synonymous variant does not change the amino acid sequence of the ATM protein. However, this variant changes the conserved c.G at the last nucleotide position of exon 47 and is predicted to have deleterious impact on splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 35402282) and an individual meeting criteria for hereditary breast and ovarian cancer syndrome (PMID: 32885271). This variant has been identified in 1/251310 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 22, 2017	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 18, 2019	The ATM c.6975G>C; p.Ala2325= variant (rs556778314), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 233023). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant occurring in the last nucleotide of exon 47, which is part of the consensus splice site for this exon. Computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2019	Not observed at a significant frequency in large population cohorts (Lek 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 25186949, 28779002) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 18, 2022	- -

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 24, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	This sequence change affects codon 2325 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. This variant also falls at the last nucleotide of exon 47, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individual(s) with breast cancer (PMID: 32885271). ClinVar contains an entry for this variant (Variation ID: 233023). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 30, 2024

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 08, 2023

Variant summary: ATM c.6975G>C (p.Ala2325Ala) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict the variant may have an impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251310 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6975G>C has been reported in the literature in an individual referred for cancer testing, based on clinical indication of hereditary breast and ovarian cancer (Lerner-Ellis_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or Cancer. To our knowledge, no 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 and classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Ala2325= variant has not been reported in the literature in individuals with ATM-related cancers, but it was identified in in one case of Ewings sarcoma (Crompton 20149). The variant was also identified in dbSNP (ID: rs556778314) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Ambry Genetics, GeneDx, Invitae, Color, and True Health Diagnostics), Clinvitae (3x), and Cosmic (in Ewings sarcoma). The variant was not identified in COGR, MutDB, LOVD 3.0, or ATM-LOVD database. The variant was identified in control databases in 1 of 246072 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Non-Finnish) in 1 of 111558 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ala2325= variant is not expected to have clinical significance because it does not result in a change of amino acid. The c.6975G>C variant occurs in the last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. This information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	20
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs556778314; hg19: chr11-108196952; COSMIC: COSV53753361; COSMIC: COSV53753361;