Submissions for variant NM_000051.4(ATM):c.9166G>T (p.Val3056Leu)

gnomAD frequency: 0.00001  dbSNP: rs371767164

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589071	SCV000209673	uncertain significance	not provided	2022-06-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23532176)
Ambry Genetics	RCV000159672	SCV000214859	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-12	criteria provided, single submitter	clinical testing	The p.V3056L variant (also known as c.9166G>T), located in coding exon 62 of the ATM gene, results from a G to T substitution at nucleotide position 9166. The valine at codon 3056 is replaced by leucine, an amino acid with highly similar properties. This alteration has been detected in the germline of 1/302 pancreatic ductal adenocarcinoma patients tested with a 25-gene panel (Chaffee KG et al. Genet. Med., 2018 01;20:119-127) and in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration has also been reported in the germline of 1/516 chronic lymphocytic leukemia patients and 0/8920 ethnically matched normal population control subjects of European descent (Tiao G et al. Leukemia, 2017 10;31:2244-2247). This amino acid position is highly 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.
Invitae	RCV000200661	SCV000254162	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3056 of the ATM protein (p.Val3056Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer and breast and/or ovarian cancer (PMID: 28726808, 29522266). ClinVar contains an entry for this variant (Variation ID: 181908). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV000589071	SCV000694391	uncertain significance	not provided	2016-01-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000200661	SCV000792420	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000200661	SCV000838626	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159672	SCV000911649	likely benign	Hereditary cancer-predisposing syndrome	2016-04-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589071	SCV002010772	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159672	SCV002530747	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003398820	SCV004120210	uncertain significance	ATM-related condition	2023-03-21	criteria provided, single submitter	clinical testing	The ATM c.9166G>T variant is predicted to result in the amino acid substitution p.Val3056Leu. This variant has been reported in an individual with pancreatic and an individual with breast and/or ovarian cancer (Table S2, Chaffee et al. 2018. PubMed ID: 28726808; Table S1, Hauke et al. 2018. PubMed ID: 29522266). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/181908/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003467224	SCV004209494	uncertain significance	Familial cancer of breast	2023-09-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000200661	SCV002083310	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-20	no assertion criteria provided	clinical testing