Submissions for variant NM_000051.4(ATM):c.1914_1929dup (p.Ser644delinsArgTer)

dbSNP: rs864622415

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206738	SCV000260555	pathogenic	Ataxia-telangiectasia syndrome	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser644Argfs*2) 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 not present in population databases (gnomAD no frequency). 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: 220196). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000581218	SCV000687344	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-20	criteria provided, single submitter	clinical testing	This variant inserts 16 nucleotides in exon 13 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
GeneDx	RCV000627508	SCV000748508	pathogenic	not provided	2018-03-15	criteria provided, single submitter	clinical testing	The c.1914_1929dup16 pathogenic variant in the ATM gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1914_1929dup16 variant causes a frameshift starting with codon Serine 644, changes this amino acid to a Arginine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Ser644ArgfsX2. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1914_1929dup16 variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1914_1929dup16 as a pathogenic variant.
Ambry Genetics	RCV000581218	SCV001174294	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-17	criteria provided, single submitter	clinical testing	The c.1914_1929dup16 variant, located in coding exon 12 of the ATM gene, results from a duplication of AGATAAAGAAGAACTT at nucleotide position 1914, causing a translational frameshift with a predicted alternate stop codon (p.S644Rfs*2). 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.
Myriad Genetics, Inc.	RCV004020526	SCV004932566	pathogenic	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.