Submissions for variant NM_000051.4(ATM):c.1931C>A (p.Ser644Ter)

dbSNP: rs768362387

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222313	SCV000278014	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	clinical testing	The p.S644* pathogenic mutation (also known as c.1931C>A), located in coding exon 12 of the ATM gene, results from a C to A substitution at nucleotide position 1931. This changes the amino acid from a serine to a stop codon within coding exon 12. This mutation has been reported in conjunction with a second pathogenic mutation in an individual with ataxia telangiectasia (A-T) (Li A and Swift M. Am J Med Genet. 2000 May 29;92(3):170-7) as well as in individuals with pancreatic cancer and in individuals with gastric cancer (Grant RC et al. Hum Genomics. 2013 Apr 5;7:11; Helgason H et al Nat. Genet. 2015 Aug;47(8):906-10). 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	RCV000482158	SCV000568316	pathogenic	not provided	2023-08-24	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with ATM-related cancers (Grant et al., 2013; Roberts et al., 2016); Observed with a second ATM variant in a patient with ataxia-telangiectasia (Li et al., 2000); This variant is associated with the following publications: (PMID: 27304073, 26658419, 25525159, 23561644, 26546047, 26098866, 28246015, 30507471, Jones2018[article], 25479140, 10817650)
Counsyl	RCV000576759	SCV000678107	likely pathogenic	Ataxia-telangiectasia syndrome	2017-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000576759	SCV000825216	pathogenic	Ataxia-telangiectasia syndrome	2023-04-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 233607). This premature translational stop signal has been observed in individual(s) with gastric cancer, pancreatic cancer, and ataxia telangiectasia (PMID: 10817650, 23561644, 25479140, 26098866). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser644*) 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	RCV000762815	SCV000893173	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222313	SCV001734339	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 13 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with pancreatic cancer (PMID: 23561644, 25479140) and has been shown to be associated with an increased risk of gastric cancer in the Icelandic population (PMID: 26098866). This variant has been reported in an individual affected with ataxia-telangiectasia (PMID: 10817650). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235146	SCV003934459	pathogenic	Malignant tumor of breast	2023-05-30	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1931C>A (p.Ser644X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanisms for disease. Another variant resulting in the same termination codon is classified as pathogenic in ClinVar (c.1931C>G). The variant was absent in 251128 control chromosomes (gnomAD). c.1931C>A has been reported in the literature in compound heterozygous individual(s) affected with Ataxia-Telangiectasia (Li_2000). The following publication has been ascertained in the context of this evaluation (PMID: 10817650). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV004020689	SCV004931354	pathogenic	Familial cancer of breast	2024-01-17	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.