Submissions for variant NM_000051.4(ATM):c.478T>C (p.Ser160Pro)

gnomAD frequency: 0.00001  dbSNP: rs761170769

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813036	SCV000953369	uncertain significance	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 160 of the ATM protein (p.Ser160Pro). This variant is present in population databases (rs761170769, gnomAD 0.0009%). 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: 656583). 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.
Ambry Genetics	RCV001023049	SCV001184865	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-13	criteria provided, single submitter	clinical testing	The p.S160P variant (also known as c.478T>C), located in coding exon 4 of the ATM gene, results from a T to C substitution at nucleotide position 478. The serine at codon 160 is replaced by proline, an amino acid with similar properties. This amino acid position is not 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.
Baylor Genetics	RCV003461214	SCV004207728	uncertain significance	Familial cancer of breast	2023-08-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001023049	SCV004356909	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 160 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251340 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355011	SCV001549765	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The ATM p.Ser160Pro variant was not identified in ClinVar or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs761170769) but the clinical significance is unknown. The variant was identified in control databases in 1 of 246110 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the in the European non-Finnish population in 1 of 111598 chromosomes (0.000009) while not observed in the following population: African, Latino, Ashkenazi Jewish, East Asian, European Finnish, South Asian, or Other populations. The variant was observed in our laboratory in trans with a pathogenic variant (ATM, p.Tyr137*) in a patient who did not have ataxia- telangiectasia suggesting that the p.Ser160Pro variant is not of clinical significance. One publication provided evidence that the p.Ser160Pro variant is not disease-causing as it was found in 1 of 17838 control chromosomes and absent in 1290 proband chromosomes of patients with chronic lymphocytic leukemia (Tiao et al, 2017). The p.Ser160 residue is conserved in mammals but not in more distantly related organisms. Four out of four computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.