rs758852420

Positions:

• chr11-108304808-TCTCGC-TA
• chr11-108304808-TCTCGC-TC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.5631_5635delinsA​(p.Phe1877LeufsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.26

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108304809-CTCGC-A is Pathogenic according to our data. Variant chr11-108304809-CTCGC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.5631_5635delinsA	p.Phe1877LeufsTer39	frameshift_variant	37/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5631_5635delinsA	p.Phe1877LeufsTer39	frameshift_variant	37/63		NM_000051.4	ENSP00000501606	P1

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed frameshift variant c.5631_5635delCTCGCinsAp.Phe1877LeufsTer39 in the ATM gene has been reported previously in compound heterozygous state in an individual with ataxia-telangiectasia Babaei M, et al., 2005. This variant is absent in the gnomAD Exomes. This variant causes a frameshift starting with codon Phenylalanine 1878, changes this amino acid to Leucine residue, and creates a premature Stop codon at position 39 of the new reading frame, denoted p.Phe1877LeufsTer39. It is submitted to ClinVar as Pathogenic/Likely pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. 5. However study on multiple affected individuals and functional studies on the pathogenicity of the variant is unavailable. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Phe1877Leufs*39) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 15843990). ClinVar contains an entry for this variant (Variation ID: 233573). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2018	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 25, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 06, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 16, 2024	This variant deletes 5 nucleotides and inserts 1 new nucleotide in exon 37 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 15843990, 35729272). This variant has also been reported in individuals affected with triple negative breast cancer (DOI: 10.1101/2022.05.31.22275080). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 06, 2022	The c.5631_5635delCTCGCinsA pathogenic mutation, located in coding exon 36 of the ATM gene, results from the deletion of 5 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.F1877Lfs*39). This alteration, described as c.5631_5635delCTCGC+5639_5640insA, has been reported in two individuals from a cohort of Iranian ataxia-telangiectasia patients (Babaei M et al, Hum. Genet. 2005 Jul; 117(2-3):101-6) as well as in three individuals from an Indian ataxia-telangiectasia patient cohort (Rawat A et al, Sci Rep. 2022 03;12(1):4036). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The frameshift variant c.5631_5635delinsA (p.Phe1877LeufsTer39) in ATM has been reported in heterozygous state in individuals affected with ataxiatelangiectasia (Babaei M et al.). The p.Phe1877LeufsTer39 variant is novel in the gnomAD Exomes database. It has been submitted to ClinVar as Pathogenic and Likely Pathogenic. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-offunction variants in ATM are known to be pathogenic (Huang Y et al.). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2019

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15843990) -

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: rs758852420; hg19: chr11-108175536;