Submissions for variant NM_000051.4(ATM):c.6114C>G (p.His2038Gln)

dbSNP: rs774993357

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219254	SCV000276456	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.H2038Q variant (also known as c.6114C>G), located in coding exon 41 of the ATM gene, results from a C to G substitution at nucleotide position 6114. The histidine at codon 2038 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000482636	SCV000572203	uncertain significance	not provided	2017-12-21	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.6114C>G at the cDNA level, p.His2038Gln (H2038Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAC>CAG). This variant was identified in a cohort of 1250 individuals with personal history of Lynch syndrome-associated cancer and/or polyps undergoing genetic testing for Lynch syndrome using a multi-gene panel (Yurgelun 2015). ATM His2038Gln was not observed in large population cohorts (Lek 2016). ATM His2038Gln is located in the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM His2038Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628144	SCV000749037	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2038 of the ATM protein (p.His2038Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 232340). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000219254	SCV000903698	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-04	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465573	SCV002760729	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567598	SCV005055869	uncertain significance	Familial cancer of breast	2024-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002465573	SCV005204188	uncertain significance	not specified	2024-06-28	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6114C>G (p.His2038Gln) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251382 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6114C>G has been reported in the literature in individuals affected with features of Lynch syndrome without evidence of causality (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 232340). Based on the evidence outlined above, the variant was classified as uncertain significance.