Submissions for variant NM_000051.4(ATM):c.392C>G (p.Ser131Ter)

dbSNP: rs1363726955

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657718	SCV000779467	likely pathogenic	not provided	2017-04-07	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.392C>G at the cDNA level and p.Ser131Ter (S131X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered likely pathogenic.
Ambry Genetics	RCV001021461	SCV001183079	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-29	criteria provided, single submitter	clinical testing	The p.S131* pathogenic mutation (also known as c.392C>G), located in coding exon 4 of the ATM gene, results from a C to G substitution at nucleotide position 392. This changes the amino acid from a serine to a stop codon within coding exon 4. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054804	SCV001219157	pathogenic	Ataxia-telangiectasia syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser131*) 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 545994). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001021461	SCV001342249	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-02	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics	RCV003465428	SCV004210148	likely pathogenic	Familial cancer of breast	2023-07-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003465428	SCV004932055	pathogenic	Familial cancer of breast	2024-01-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.