Variant: NM_000051.4(ATM):c.748C>T (p.Arg250Ter)

CA336868

216024 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 4d278908-90bb-42c7-99e9-dac5f9de7e14

Approved on: 2024-11-26

Published on: 2025-01-13

HGVS expressions

NM_000051.4:c.748C>T
NM_000051.4(ATM):c.748C>T (p.Arg250Ter)
NC_000011.10:g.108244873C>T
CM000673.2:g.108244873C>T
NC_000011.9:g.108115600C>T
CM000673.1:g.108115600C>T
NC_000011.8:g.107620810C>T
NG_009830.1:g.27042C>T
ENST00000452508.7:c.748C>T
ENST00000713593.1:c.*219C>T
ENST00000278616.9:c.748C>T
ENST00000682430.1:n.847C>T
ENST00000682516.1:n.882C>T
ENST00000682956.1:n.882C>T
ENST00000683100.1:n.3095C>T
ENST00000683174.1:n.898C>T
ENST00000683605.1:n.243C>T
ENST00000684037.1:c.748C>T
ENST00000684061.1:n.882C>T
ENST00000684179.1:n.717C>T
ENST00000527805.6:c.748C>T
ENST00000675595.1:c.583C>T
ENST00000675843.1:c.748C>T
ENST00000278616.8:c.748C>T
ENST00000452508.6:c.748C>T
ENST00000527805.5:c.748C>T
NM_000051.3:c.748C>T
NM_001351834.1:c.748C>T
NM_001351834.2:c.748C>T

Pathogenic

• Met criteria codes: PM5_Supporting PM2_Supporting PM3_Very Strong PVS1

• Not Met criteria codes: BS1 PS3 BA1

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.3.0

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.748C>T (p.Arg250*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in numerous individuals with Ataxia-Telangiectasia (PMIDs: 10330348, 12552559, 20840352, 21778326, 22006793, 26896185, 30816533, 31611883). The highest population minor allele frequency in gnomAD v2.1.1 0.00003 (1/34560) which meets the PM2 threshold of n≤1 alleles when sub-population frequency is >0.00001 (PM2_Supporting met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_VeryStrong, PM2_Supporting)

Met criteria codes

• PM5_Supporting: This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious (PM5_Supporting)
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 0.00003 (1/34560) which meets the PM2 threshold of n≤1 alleles when sub-population frequency is >0.00001 (PM2_Supporting met).
• PM3_Very Strong: This variant has been detected in numerous individuals with Ataxia-Telangiectasia PMID: 20840352, PMID: 26896183 PMID: 30816533 PMID: 31611883 PMID: 22006793 PMID: 21778326 PMID: 12552559 PMID: 10330348
• PVS1: The c.748C>T (p.Arg250Ter) variant in ATM is a nonsense variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

Not Met criteria codes

• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: RT-PCR of patient RNA identified skipping of out of frame exon 7 (described as exon 9); however in the absence of quantification the significance of these findings are unclear. PMID: 22006793 . PMID: 10330348
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline