rs1064792939

Variant names:

• chr11-108301789-GGTCTCTTA-TGTTTG
• rs1064792939
• NM_000051.4:c.5319_5319+8delGGTCTCTTAinsTGTTTG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000051.4(ATM):​c.5319_5319+8delGGTCTCTTAinsTGTTTG​(p.Lys1773delins???) variant causes a splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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, missense, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 8.18

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.5319_5319+8delGGTCTCTTAinsTGTTTG	p.Lys1773delins???	splice_donor_variant, missense_variant, splice_region_variant, intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5319_5319+8delGGTCTCTTAinsTGTTTG	p.Lys1773delins???	splice_donor_variant, missense_variant, splice_region_variant, intron_variant			NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Pathogenic:1 Uncertain:1

Oct 08, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 02, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:1

Feb 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 407532). This variant is not present in population databases (ExAC no frequency). This variant is a complex sequence change involving the donor splice site of intron 35. It results in a nucleotide substitution at the last nucleotide of exon 35 of the ATM coding sequence, which is part of the consensus splice site for this exon. -

not provided Uncertain:1

Feb 02, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.5319_5319+8delGGTCTCTTAinsTGTTTG at the cDNA level. The surrounding sequence is GAAAAAA[delGgtctctta][insTgtttg]agta, where the capital letters are exonic and lower case are intronic. Although this combined deletion and insertion spans the intron/exon boundary including the canonical splice site, a 'GT' is retained at the canonical +1 and +2 positions. In silico analyses, which include splice predictors and evolutionary conservation, are uninformative in their assessment as to whether or not the variant is damaging; therefore, in the absence of RNA or functional studies, the actual effect of this variant is unknown. ATM c.5319_5319+8delGGTCTCTTAinsTGTTTG has not, to our knowledge, been reported in the literature as pathogenic or benign. This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether this variant is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 31, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5319_5319+8delinsTGTTTG variant results from a deletion of 9 nucleotides and insertion of 6 nucleotides between positions c.5319 and c.5319+8. This variant involves the last nucleotide of coding exon 35 of the ATM gene but maintains the sequence of the canonical positions at this donor site. The last nucleotide is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064792939; hg19: chr11-108172516;