Submissions for variant NM_000051.4(ATM):c.4868T>C (p.Leu1623Pro)

dbSNP: rs786203017

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166136	SCV000216908	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-23	criteria provided, single submitter	clinical testing	The p.L1623P variant (also known as c.4868T>C), located in coding exon 31 of the ATM gene, results from a T to C substitution at nucleotide position 4868. The leucine at codon 1623 is replaced by proline, an amino acid with similar properties. This amino acid position is poorly 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	RCV000200850	SCV000254116	uncertain significance	Ataxia-telangiectasia syndrome	2023-09-19	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 186527). This missense change has been observed in individual(s) with pancreatic and endometrial cancer and lymphoma (PMID: 29360161). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1623 of the ATM protein (p.Leu1623Pro). 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.
GeneDx	RCV000485111	SCV000567753	uncertain significance	not provided	2015-08-26	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4868T>C at the cDNA level, p.Leu1623Pro (L1623P) at the protein level, and results in the change of a Leucine to a Proline (CTA>CCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu1623Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Leu1623Pro occurs at a position that is not conserved and is not located in a known functional domain (Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Leu1623Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290687	SCV001478824	uncertain significance	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4868T>C (p.Leu1623Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251362 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4868T>C has been reported in the literature in at-least one individual affected with Pancreatic/lymphoma/uterine cancer, no reported family history of cancer and not fulfilling the NCCN criteria for Lynch and HBOC (Dudley_2018). This report does not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia, Breast or any ATM associated cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000166136	SCV004360999	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 1623 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 not been identified 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.
Baylor Genetics	RCV004567295	SCV005057007	uncertain significance	Familial cancer of breast	2024-02-07	criteria provided, single submitter	clinical testing