Submissions for variant NM_000051.4(ATM):c.680C>T (p.Ser227Leu)

gnomAD frequency: 0.00001  dbSNP: rs762998620

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569541	SCV000672624	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-24	criteria provided, single submitter	clinical testing	The p.S227L variant (also known as c.680C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 680. The serine at codon 227 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569541	SCV000682366	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 227 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 observed in individuals affected with breast cancer (Color Health internal data), prostate cancer (PMID: 33436325), glioblastoma multiforme (PMID: 26689913), as well as in an individual referred for hereditary cancer genetic testing (PMID: 31159747). This variant has been identified in 1/251126 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.
GeneKor MSA	RCV000569541	SCV000821867	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796269	SCV000935774	pathogenic	Ataxia-telangiectasia syndrome	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 227 of the ATM protein (p.Ser227Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs762998620, gnomAD 0.007%). This missense change has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer, or prostate cancer (PMID: 31159747, 33436325). ClinVar contains an entry for this variant (Variation ID: 485170). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. Studies have shown that this missense change results in skipping of exon 7, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002222556	SCV002499809	likely pathogenic	not provided	2025-03-06	criteria provided, single submitter	clinical testing	RNA studies demonstrate a damaging effect: aberrant splicing leading to out-of-frame exon skipping, resulting in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (External communication with an outside laboratory); Observed in individuals with prostate cancer, glioblastoma, or premature ovarian insuffiency (PMID: 33436325, 26689913, 38649916); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 38649916, 31159747, 26689913, 33436325)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493663	SCV004243405	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV004776440	SCV005387756	uncertain significance	Familial cancer of breast	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 227 of the ATM protein (p.Ser227Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (gnomAD). This missense change has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer, or prostate cancer (PMID: 31159747, 33436325). ClinVar contains an entry for this variant (Variation ID: 485170). In silico analysis supports that this missense variant does not alter protein structure/function . 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. Pathogenic/likely pathogenic mutations in the ATM gene cause susceptibility to breast cancer (OMIM 114480).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002222556	SCV005626061	uncertain significance	not provided	2024-04-12	criteria provided, single submitter	clinical testing