ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6919C>T (p.Leu2307Phe) (rs56009889)

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Total submissions: 17
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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.
Invitae RCV000988720 SCV000153843 benign Ataxia-telangiectasia syndrome 2020-11-27 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: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Health, Inc 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,PreventionGenetics 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 Clinical Services Laboratory,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 RCV001287071 SCV001473715 likely benign none provided 2019-09-17 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

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