rs869312788

Positions:

• chr11-108332040-A-G
• chr11-108332040-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000051.4(ATM):​c.7788+3A>G variant causes a splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: ATM NM_000051.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 4.63

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108332040-A-G is Pathogenic according to our data. Variant chr11-108332040-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420257.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.7788+3A>G		splice_donor_region_variant, intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7788+3A>G		splice_donor_region_variant, intron_variant			NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2022	The c.7788+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 51 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In a study involving RNA extraction for RT-PCR and Sanger sequencing of 10 hereditary cancer genes, incomplete disruption of the natural splice site was observed for this alteration (Rofes P et al. J Mol Diagn, 2020 12;22:1453-1468). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.7788+3A>G variant it is predicted to disrupt the donor splice site for intron 52. The skipping of exon 52 predicted by default would result in an in-frame deletion of 53 codons (r. .7630_7788del, p.Leu2544_Glu2596del, PP3). Splicing studies performed by two independent laboratories with heterozygous carrier RNA from breast cancer patients confirmed the presence of the predicted transcript with a band intensity comparable to that of the wild-type band (r.7630_7927del p.Leu2544Lysfs*3, O. Díez, unpublished and PMID: 33011440). Sanger sequencing also revealed a very minor transcript corresponding to the out-of-frame skipping of exons 52 and 53 (PMID: 33011440). Although the major transcript is in frame, the skipped exon 52 is located in the FAT domain and contains the nucleotides deleted in the pathogenic in-frame deletion pathogenic variant c.7638_7646del. These RNA results and their expected consequence allow for a funtional supporting code (PS3_Supporting). The c.7788+3A>G variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It has been reported in one ataxia-telangiectasia proband in trans with c.5932G > T (p.Glu1978*), which awards it with 1 point as per ClinGen SVI Recommendation for in trans Criterion (PM3, De Stefano, 2016 https://doi.org/10.1515/labmed-2016-0018). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PM3 + PP3 + PS3_Supporting (PMID: 33280026). -

Ataxia-telangiectasia syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

This sequence change falls in intron 52 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 33011440; De Stefano et al. 2016. J Lab Med. 40(4): 255–261). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 420257). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 33011440). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2023

Intronic variant demonstrated to result in the in-frame skipping of exon 52, which includes the critical FAT domain, as well as out-of-frame exons 52-53, and exon 53 (Stracker et al., 2014; Rofes et al., 2020); Non-canonical splice site variant expected to result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33011440, 33280026, 23532176, DeStefano2016[Article]) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 07, 2017

Variant summary: The ATM c.7788+3A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict the weakening or loss of a 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 119830 control chromosomes and was reported in one patient with AT along with a truncating ATM mutation and one patient with ovarian cancer in the literature. One clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. Taken together, this variant is classified as VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs869312788; hg19: chr11-108202767;