Submissions for variant NM_000051.4(ATM):c.5765C>A (p.Pro1922His)

dbSNP: rs751792004

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216727	SCV000277337	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	The p.P1922H variant (also known as c.5765C>A), located in coding exon 38 of the ATM gene, results from a C to A substitution at nucleotide position 5765. The proline at codon 1922 is replaced by histidine, 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.
Color Diagnostics, LLC DBA Color Health	RCV000216727	SCV000913972	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces proline with histidine at codon 1922 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 1/245598 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812353	SCV000952664	uncertain significance	Ataxia-telangiectasia syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 1922 of the ATM protein (p.Pro1922His). This variant is present in population databases (rs751792004, 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: 233041). 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 disruptive. 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.
Sema4, Sema4	RCV000216727	SCV002529223	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
GeneDx	RCV004591006	SCV005080474	uncertain significance	not provided	2023-06-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with kidney cancer whose testing also identified ATM p.(G1925E) (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 29684080)
PreventionGenetics, part of Exact Sciences	RCV004725088	SCV005337958	uncertain significance	ATM-related disorder	2024-05-30	no assertion criteria provided	clinical testing	The ATM c.5765C>A variant is predicted to result in the amino acid substitution p.Pro1922His. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is interpreted as uncertain clinical significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/233041/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.