Submissions for variant NM_000051.4(ATM):c.5750G>C (p.Arg1917Thr)

gnomAD frequency: 0.00001  dbSNP: rs377289524

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129190	SCV000183928	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-28	criteria provided, single submitter	clinical testing	The p.R1917T variant (also known as c.5750G>C), located in coding exon 37 of the ATM gene, results from a G to C substitution at nucleotide position 5750. The arginine at codon 1917 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was identified in a French breast cancer patient (Renault AL et al. Breast Cancer Res., 2018 04;20:28). Another study identified this variant in a patient with cutaneous melanoma and was reportedly identified in the patient's sister with cutaneous melanoma and father with a history of prostate cancer, bladder cancer, colorectal cancer and uveal melanoma. This same study identified this variant in second patient with multiple primary melanomas; however this patient was also positive for a germline MITF p.Glu218Lys alteration (Pastorino L et al. Cancers (Basel), 2020 04;12:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000471458	SCV000547047	uncertain significance	Ataxia-telangiectasia syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1917 of the ATM protein (p.Arg1917Thr). This variant is present in population databases (rs377289524, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or melanoma (PMID: 30303537, 32325837, 34262154). ClinVar contains an entry for this variant (Variation ID: 140925). 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.
GeneDx	RCV000486854	SCV000567742	uncertain significance	not provided	2023-08-02	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 individuals with breast and other cancers (Renault et al., 2018; Girard et al., 2019; Pastorino et al., 2020; Dalmasso et al., 2021); This variant is associated with the following publications: (PMID: 29665859, 30303537, 32325837, 34262154)
Color Diagnostics, LLC DBA Color Health	RCV000129190	SCV000687638	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with threonine at codon 1917 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 29665859) or melanoma (PMID: 32325837, 34262154). This variant has been identified in 2/251008 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	RCV002271412	SCV002555888	uncertain significance	not specified	2022-06-15	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5750G>C (p.Arg1917Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251008 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5750G>C has been reported in the literature in individuals affected with and/or undergoing testing for breast cancer/melanoma (example, Renault_2018, Girard_2019, Pastorino_2020, Dalmasso_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.
Baylor Genetics	RCV003467104	SCV004207106	uncertain significance	Familial cancer of breast	2024-03-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000471458	SCV002077293	uncertain significance	Ataxia-telangiectasia syndrome	2021-06-22	no assertion criteria provided	clinical testing