Submissions for variant NM_000051.4(ATM):c.6919C>T (p.Leu2307Phe)

gnomAD frequency: 0.00035  dbSNP: rs56009889

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120155	SCV000149144	benign	not specified	2015-11-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000988720	SCV000153843	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115235	SCV000183909	benign	Hereditary cancer-predisposing syndrome	2014-07-12	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000586678	SCV000342311	uncertain significance	not provided	2016-05-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120155	SCV000593490	benign	not specified	2019-07-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115235	SCV000682374	likely benign	Hereditary cancer-predisposing syndrome	2014-12-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586678	SCV000694338	benign	not provided	2017-01-03	criteria provided, single submitter	clinical testing	Variant summary: This c.6919C>T variant affects a conserved nucleotide, resulting in conservative amino acid change from Leu to Phe. 3/5 in-silico tools predict this variant to be damaging. This variant has been reported in patients with breast cancer, ovarian cancer, melanoma, lung cancer, CLL or Hodgkin's disease; however, without evidence on co-segregation analysis. In one family with familial CLL, this variant was found in one affected brother but not in the other affected brother (Yuille_2002) (ACMG, BS4). Additionally, in a patient with a history of Lynch syndrome, the variant co-occurred with a pathogenic MSH2 variant (Yurgelun_2015) (ACMG, BP5). This variant has not been reported in patients with Ataxia-Telangiectasia (a recessive disorder). This variant was found in 140/128300 control chromosomes including one homozygote (ACMG, BS2) from multiple ethnic populations at a frequency of 0.0010912, which is about 2 times greater than the maximal expected frequency of a pathogenic allele (0.0005001) in this gene, suggesting this variant is benign (ACMG, BS1). Multiple case-control studies have shown that this variant was not associated with breast cancer, except one study (Haiman_2013, OR=4.133 in mixed ethnic populations, OR=9.805 in European American). The study (Haiman_2013), however, did not provide confidence interval and distribution of the variant is patient and control cohorts appear to be small, not suggesting a believable odds ratio. Multiple clinical laboratories classified this variant as likely benign/benign (ACMG BP6). Taken together, this variant was classified as a Benign variant.
PreventionGenetics, part of Exact Sciences	RCV000120155	SCV000805609	benign	not specified	2017-05-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000988720	SCV001138554	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000988720	SCV001260752	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586678	SCV001473715	likely benign	not provided	2019-09-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115235	SCV002538594	benign	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115235	SCV002819237	benign	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120155	SCV004024716	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586678	SCV004133269	benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ATM: BS1, BS2
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586678	SCV004222064	benign	not provided	2021-07-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492465	SCV004239416	benign	Breast and/or ovarian cancer	2023-04-26	criteria provided, single submitter	clinical testing
ITMI	RCV000120155	SCV000084296	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000115235	SCV000787878	likely benign	Hereditary cancer-predisposing syndrome	2017-08-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000988720	SCV001452127	benign	Ataxia-telangiectasia syndrome	2020-01-07	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354648	SCV001549313	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Leu2307Phe variant was identified in 18 of 2820 proband chromosomes (frequency: 0.006) from British, Brazilian, French, Dutch and American individuals or families with chronic lymphocytic leukemia or breast cancer (Yuille 2002, Lähdesmäki 2004, Tiao 2017, Mangone 2015, Broeks 2008, LaPaglia 2010). The variant was also identified in the following databases: dbSNP (ID: rs56009889) as “With other allele”, ClinVar and Clinvitae (3x classified as benign by GeneDx, Invitae, Ambry Genetics; 1x classified as uncertain significance by EGL Genetic Diagnostics; 1x classification not provided by ITMI), and COSMIC (1x confirmed somatic in hemangioblastoma). The variant was not identified in GeneInsight-COGR, MutDB, LOVD 3.0, or the ATM-LOVD databases. The variant was identified in control databases in 356 of 277088 chromosomes (3 homozygous) at a frequency of 0.001 in the following populations: Ashkenazi Jewish in 310 of 10148 chromosomes (freq 0.03); population classified as “other” in 9 of 6458 chromosomes (freq 0.001); European non-Finnish in 32 of 126602 chromosomes (freq 0.0002); Latino in 3 of 34416 chromosomes (freq 0.00009); African in 2 of 24036 chromosomes (freq 0.00008) increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In a study of Brazilian patients with sporadic breast cancer this variant was found in two patients, one of who also harboured a second ATM variant (p.Thr935Arg) and demonstrated loss of heterozygosity in tumour DNA (Mangone 2015). This variant was found together with an inactivating BRCA2 nonsense variant in a prostate cancer patient with exceptional response to high-dose testosterone therapy (Tepley 2017). The p.Leu2307Phe variant has also been reported in a French breast cancer patient with a family history of both breast cancer and hematological malignancy (LaPaglia 2010). In a study of ATM mutations in European familial chronic lymphocytic leukemia patients this variant was found in one patient but not in a brother with disease (Yuille 2002). The p.Leu2307Phe residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000120155	SCV001740317	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000120155	SCV001808814	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120155	SCV001906088	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000120155	SCV001920111	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000120155	SCV001931795	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586678	SCV001953167	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586678	SCV001975959	likely benign	not provided		no assertion criteria provided	clinical testing