Submissions for variant NM_000051.4(ATM):c.8120C>G (p.Ser2707Cys)

gnomAD frequency: 0.00002  dbSNP: rs748016261

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204523	SCV000260658	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2707 of the ATM protein (p.Ser2707Cys). This variant is present in population databases (rs748016261, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 220257). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.
Color Diagnostics, LLC DBA Color Health	RCV000447583	SCV000537544	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000509525	SCV000569245	uncertain significance	not provided	2019-09-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in women with breast cancer, but also observed in unaffected controls (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823)
Ambry Genetics	RCV000447583	SCV000660529	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-25	criteria provided, single submitter	clinical testing	The p.S2707C variant (also known as c.8120C>G), located in coding exon 54 of the ATM gene, results from a C to G substitution at nucleotide position 8120. The serine at codon 2707 is replaced by cysteine, an amino acid with dissimilar properties. This variant has been identified in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Momozowa Y et al. Nat Commun 2018 10;9(1):4083; Wang J et al. Cancer Med, 2019 05;8:2074-2084; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Liu Y et al. Front Genet, 2023 Nov;14:1271710). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Counsyl	RCV000204523	SCV000796997	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-08	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030604	SCV001193489	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Genome-Nilou Lab	RCV000204523	SCV001781397	uncertain significance	Ataxia-telangiectasia syndrome	2021-07-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000447583	SCV002537911	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000509525	SCV002774782	uncertain significance	not provided	2021-07-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468945	SCV004210061	uncertain significance	Familial cancer of breast	2024-03-22	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000509525	SCV000606904	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000204523	SCV002076907	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739595	SCV005358345	uncertain significance	ATM-related disorder	2024-03-21	no assertion criteria provided	clinical testing	The ATM c.8120C>G variant is predicted to result in the amino acid substitution p.Ser2707Cys. This variant was reported in both female and male breast cancer patients (Supplementary Data 1 & 2 in Momozawa et al. 2018. PubMed ID: 30287823; Table S1 in Zhang et al. 2018. PubMed ID: 29905759; Table S2 in Wang et al. 2019. PubMed ID: 30982232) however, it was also reported in controls (Supplementary Data 1 in Momozawa et al. 2018. PubMed ID: 30287823; Supplemental Table 2 in Okawa et al. 2022. PubMed ID: 36243179). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as uncertain in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/220257/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.