rs1555091084

Positions:

• chr11-108280980-T-TTA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000051.4(ATM):​c.3403-15_3403-14insTA variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,556,992 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00057 (1 hom.)
• Consequence: ATM NM_000051.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.133

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 Benign. Variant got -8 ACMG points.

• BP6: Variant 11-108280980-T-TTA is Benign according to our data. Variant chr11-108280980-T-TTA is described in ClinVar as [Likely_benign]. Clinvar id is 490530.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.3403-15_3403-14insTA		splice_polypyrimidine_tract_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.3403-15_3403-14insTA		splice_polypyrimidine_tract_variant, intron_variant			NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 32 AN: 151728 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000857

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000556 AC: 129 AN: 231976 Hom.: 0 AF XY: 0.000548 AC XY: 69 AN XY: 125826

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000673

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00114

Gnomad NFE exome AF: 0.000468

Gnomad OTH exome AF: 0.000898

GnomAD4 exome AF: 0.000570 AC: 801 AN: 1405146 Hom.: 1 Cov.: 31 AF XY: 0.000564 AC XY: 395 AN XY: 700236

Gnomad4 AFR exome AF: 0.000443

Gnomad4 AMR exome AF: 0.000673

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.000382

Gnomad4 FIN exome AF: 0.000852

Gnomad4 NFE exome AF: 0.000550

Gnomad4 OTH exome AF: 0.000567

GnomAD4 genome AF: 0.000211 AC: 32 AN: 151846 Hom.: 0 Cov.: 0 AF XY: 0.000242 AC XY: 18 AN XY: 74258

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000857

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00265 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 19, 2022

- -

ATM-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial ovarian cancer Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM c.3403-15_3403-14insTA variant was identified in the following databases: dbSNP (ID: rs3218681) “With Benign, other allele”, and in control databases in 144695 (40554 homozygous) of 258930 chromosomes at a frequency of 0.6 (Genome Aggregation Consortium Feb 27, 2017), falling on 3 transcripts with a population breakdown of: South Asian in 16377 (5070 homozygous) of 26642 chromosomes (freq: 0.6), European (Finnish) in 14916 (4483 homozygous) of 24280 chromosomes (freq: 0.6), Latino in 19186 (5780 homozygous) of 31316 chromosomes (freq: 0.6), Ashkenazi Jewish in 5646 (1697 homozygous) of 9232 chromosomes (freq: 0.6), Other in 3528 (1050 homozygous) of 5964 chromosomes (freq: 0.6), European (Non-Finnish) in 67483 (18810 homozygous) of 119980 chromosomes (freq: 0.6), African in 10689 (2402 homozygous) of 23444 chromosomes (freq: 0.5), and East Asian in 6870 (1262 homozygous) of 18072 chromosomes (freq: 0.4). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 16, 2020

- -

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: rs1555091084; hg19: chr11-108151707;