Submissions for variant NM_000051.4(ATM):c.5633C>T (p.Ser1878Leu)

gnomAD frequency: 0.00001  dbSNP: rs758908522

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489997	SCV000577000	uncertain significance	not provided	2024-12-16	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of breast cancer, as well as in unaffected controls (PMID: 19347964, 19781682, 28652578); This variant is associated with the following publications: (PMID: 28652578, 19347964, 19781682)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546553	SCV000622608	likely benign	Ataxia-telangiectasia syndrome	2024-12-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569421	SCV000667861	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-15	criteria provided, single submitter	clinical testing	The p.S1878L variant (also known as c.5633C>T), located in coding exon 36 of the ATM gene, results from a C to T substitution at nucleotide position 5633. The serine at codon 1878 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in 0/4112 breast cancer cases and 1/2399 controls (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46). This amino acid position is 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	RCV000569421	SCV000687631	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 1878 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 reported in an individual affected with breast cancer (PMID: 36200007). This variant has been identified in 9/248308 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780900	SCV000918536	uncertain significance	not specified	2022-04-28	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5633C>T (p.Ser1878Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 248308 control chromosomes in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5633C>T has been reported in the literature in individuals affected with breast cancer and in unaffected controls (example, Tiao_2017, Tavtigian_2009, Nguyen-Dumont_2009, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Likely Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Athena Diagnostics	RCV000489997	SCV001879501	uncertain significance	not provided	2021-01-25	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000546553	SCV002767300	uncertain significance	Ataxia-telangiectasia syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMID: 20301790, 27884168). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (7 heterozygotes, 1 homozygote). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity in autosomal recessive Ataxia-telangiectasia. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as VUS multiple times and once as likely benign (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Myriad Genetics, Inc.	RCV003316640	SCV004018655	likely benign	Familial cancer of breast	2023-06-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000489997	SCV004221176	uncertain significance	not provided	2021-01-25	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with chronic lymphocytic leukemia (PMID: 28652578 (2017)). This variant has also been reported in unaffected cancer free individuals (PMID: 19781682 (2009), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.00016 (5/30566 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000546553	SCV001452325	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing