Submissions for variant NM_000051.4(ATM):c.3265G>T (p.Ala1089Ser)

gnomAD frequency: 0.00001  dbSNP: rs730881358

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159708	SCV000209720	uncertain significance	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or Lynch syndrome, including patients who also harbored variants in BRCA1 and MLH1 respectively (PMID: 34326862, 28779002, 33383211); This variant is associated with the following publications: (PMID: 22210328, 28069802, 28779002, 33383211, 35047863, 19781682, 34326862)
Ambry Genetics	RCV000215659	SCV000274769	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.A1089S variant (also known as c.3265G>T), located in coding exon 21 of the ATM gene, results from a G to T substitution at nucleotide position 3265. The alanine at codon 1089 is replaced by serine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228095	SCV000282927	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1089 of the ATM protein (p.Ala1089Ser). This variant is present in population databases (rs730881358, gnomAD 0.003%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 35047863). ClinVar contains an entry for this variant (Variation ID: 181941). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000215659	SCV000682112	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1089 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and in unaffected individuals (PMID: 28779002, 33471991). This variant has been identified in 3/276880 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779762	SCV000916539	uncertain significance	not specified	2024-09-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3265G>T (p.Ala1089Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251164 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3265G>T has been reported in the literature in at least one individual affected with pancreatic cancer (e.g., Yu_2021). It has also been reported in a cohort of individuals who were suspected to have a hereditary cancer syndrome based on personal or family history (e..g, Bhai_2021). However, these report(s) do not provide unequivocal conclusions about association of the variant with cancer. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1958T>G, p.Leu653Arg), providing supporting evidence for a benign role (Pope_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 33383211, 35047863). ClinVar contains an entry for this variant (Variation ID: 181941). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000215659	SCV002535868	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159708	SCV003799680	uncertain significance	not provided	2022-07-08	criteria provided, single submitter	clinical testing	The ATM c.3265G>T, p.Ala1089Ser variant (rs730881358), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 181941). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 1089 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.151). Due to limited information, the clinical significance of the this variant is uncertain at this time
Revvity Omics, Revvity	RCV000228095	SCV003827463	uncertain significance	Ataxia-telangiectasia syndrome	2022-11-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462072	SCV004207038	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000159708	SCV005412459	uncertain significance	not provided	2023-10-18	criteria provided, single submitter	clinical testing	BP4
Natera, Inc.	RCV000228095	SCV001457134	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551373	SCV004722626	uncertain significance	ATM-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The ATM c.3265G>T variant is predicted to result in the amino acid substitution p.Ala1089Ser. This variant was reported in individuals with breast or pancreatic cancer (Table S5, Decker et al. 2017. PubMed ID: 28779002; Fig 2B, Yu et al. 2022. PubMed ID: 35047863). This variant was also reported in an individual suspected of Lynch syndrome; however, this individual also harbored a causative germline variant in MLH1 (Case SLS6 in Table S3, Pope et al. 2021. PubMed ID: 33383211). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181941/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.