rs763470424

Positions:

• chr11-108330217-C-A
• chr11-108330217-C-G
• chr11-108330217-C-T

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.7311C>A​(p.Tyr2437*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.36

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]

ATM (HGNC:):

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 11-108330217-C-A is Pathogenic according to our data. Variant chr11-108330217-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 453669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108330217-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.7311C>A	p.Tyr2437*	stop_gained	50/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7311C>A	p.Tyr2437*	stop_gained	50/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461440 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727044

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2021	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 453669). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 16832357). This sequence change creates a premature translational stop signal (p.Tyr2437*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	This variant has been observed in an individual affected with breast cancer (Renwick A et al). This variant has been reported to the ClinVar database as Pathogenic. The c.7311C>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This sequence change creates a premature translational stop signal (p.Tyr2437*) 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 (Podralska MJ et al). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 31, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Malignant tumor of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 14, 2023

Variant summary: ATM c.7311C>A (p.Tyr2437X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250926 control chromosomes (gnomAD). c.7311C>A has been reported in the literature in individuals from a familial breast cancer family, wherein two affected individuals harbored the variant and one affected individual had the reference allele (Renwick_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2024

The p.Y2437* pathogenic mutation (also known as c.7311C>A), located in coding exon 49 of the ATM gene, results from a C to A substitution at nucleotide position 7311. This changes the amino acid from a tyrosine to a stop codon within coding exon 49. This mutation has been detected in a familial breast cancer kindred (Renwick A et al. Nat. Genet. 2006 Aug; 38(8):873-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.98
GERP RS		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs763470424; hg19: chr11-108200944;