Submissions for variant NM_000051.4(ATM):c.1631T>C (p.Leu544Ser)

gnomAD frequency: 0.00010  dbSNP: rs375754332

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164434	SCV000215073	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	The p.L544S variant (also known as c.1631T>C), located in coding exon 10 of the ATM gene, results from a T to C substitution at nucleotide position 1631. The leucine at codon 544 is replaced by serine, an amino acid with dissimilar 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.
GeneDx	RCV000588135	SCV000566873	uncertain significance	not provided	2023-09-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals undergoing multi-gene hereditary cancer panel testing (Mu et al., 2016); This variant is associated with the following publications: (PMID: 27720647)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531488	SCV000622274	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 544 of the ATM protein (p.Leu544Ser). This variant is present in population databases (rs375754332, gnomAD 0.02%). 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: 185076). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797649	SCV000694190	uncertain significance	not specified	2022-12-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1631T>C (p.Leu544Ser) 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 allele was found at a frequency of 1.2e-05 in 251334 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1631T>C in individuals affected with Breast Cancer/Ataxia Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Ten 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.
Eurofins Ntd Llc (ga)	RCV000588135	SCV000703944	uncertain significance	not provided	2016-12-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588135	SCV001249799	uncertain significance	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164434	SCV001343664	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 544 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 ATM-related disorders in the literature. This variant has been identified in 6/282740 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.
Baylor Genetics	RCV000531488	SCV001482693	uncertain significance	Ataxia-telangiectasia syndrome	2019-01-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000531488	SCV002526033	uncertain significance	Ataxia-telangiectasia syndrome	2022-04-13	criteria provided, single submitter	clinical testing	The ATM c.1631T>C (p.Leu544Ser) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL does not conclusively predict a deleterious or benign effect of this variant, and to our knowledge functional assays have not been performed. To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia or hereditary breast cancer. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel: no criteria met.
Sema4, Sema4	RCV000164434	SCV002530964	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588135	SCV002774788	uncertain significance	not provided	2021-08-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462135	SCV004207057	uncertain significance	Familial cancer of breast	2024-01-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000531488	SCV002095533	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739519	SCV005357117	uncertain significance	ATM-related disorder	2024-05-08	no assertion criteria provided	clinical testing	The ATM c.1631T>C variant is predicted to result in the amino acid substitution p.Leu544Ser. This variant has been reported in individual(s) going though hereditary cancer panel testing but no clinical information was provided (S Table 3. Mu et al 2016. PubMed ID: 27720647). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185076/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.