Submissions for variant NM_000051.4(ATM):c.6326G>A (p.Trp2109Ter)

dbSNP: rs587782114

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130633	SCV000185509	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-29	criteria provided, single submitter	clinical testing	The p.W2109* pathogenic mutation (also known as c.6326G>A) located in coding exon 42 of the ATM gene, results from a G to A substitution at nucleotide position 6326. This changes the amino acid from a tryptophan to a stop codon within coding exon 42. This mutation was detected in an ataxia-telangiectasia (A-T) patient who was later found to carry a pathogenic deep intronic mutation in trans (Cavalieri S et al. Ann. Hum. Genet. 2008 Jan;72:10-8; Cavalieri S et al. Eur. J. Hum. Genet. 2013 Jul;21:774-8). 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.
GeneDx	RCV000521744	SCV000617372	pathogenic	not provided	2017-10-03	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.6326G>A at the cDNA level and p.Trp2109Ter (W2109X) at the proteinlevel. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon(TGG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in an individual with Ataxia-Telangiectasia and found to be intrans with an ATM variant that reportedly impacts splicing (Cavalieri 2008, Porcedda 2008, Cavalieri 2013). Based oncurrently available evidence, we consider ATM Trp2109Ter to be a pathogenic variant
Invitae	RCV001857452	SCV002242122	pathogenic	Ataxia-telangiectasia syndrome	2023-07-07	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 141921). This premature translational stop signal has been observed in individual(s) with breast cancer and clinical features of ataxia-telangiectasia (PMID: 17910737, 30303537). This sequence change creates a premature translational stop signal (p.Trp2109*) 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).
Fulgent Genetics, Fulgent Genetics	RCV002492505	SCV002779961	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-04-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467150	SCV004212110	pathogenic	Familial cancer of breast	2023-01-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467150	SCV004931126	pathogenic	Familial cancer of breast	2024-01-29	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.