ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3077+4G>A (rs201222237)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213394 SCV000275928 likely benign Hereditary cancer-predisposing syndrome 2019-09-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study;RNA Studies
GeneDx RCV000430951 SCV000512152 benign not specified 2015-04-20 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 RCV000988671 SCV000546998 likely benign Ataxia-telangiectasia syndrome 2020-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000430951 SCV000694248 likely benign not specified 2021-02-26 criteria provided, single submitter clinical testing Variant summary: ATM c.3077+4G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 250438 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (5.6e-05 vs 0.001), allowing no conclusion about variant significance. c.3077+4G>A has been reported in the literature in individuals affected with Lynch Syndrome (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer. 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 (benign/likely benign n=4, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000213394 SCV000903068 likely benign Hereditary cancer-predisposing syndrome 2016-02-10 criteria provided, single submitter clinical testing
Mendelics RCV000988671 SCV001138482 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355758 SCV001550726 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM c.3077+4G>A variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch Syndrome associated cancer or colorectal polyps (Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs201222237) as “With Uncertain significance allele” and ClinVar (4x as benign by GeneDx, as likely benign by Invitae, as uncertain significance by Ambry Genetics and Integrated Genetics). The variant was not identified in Cosmic, MutDB, LOVD 3.0 or ATM-LOVD databases. The variant was identified in control databases in 17 of 276132 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 16 of 23934 chromosomes (freq: 0.00067) and Latino in 1 of 34378 chromosomes (freq: 0.00003). It was not observed in the “Other”, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish or South Asian populations. This variant was identified in our laboratory with a co-occurring pathogenic BRCA2 variant (c.3455T>G, p.Leu1152*), increasing the likelihood that the c.3077+4G>A variant does not have clinical significance. The c.3077+4G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% increased difference in splicing 3 bp upstream at the consensus splice junction. However, this information is not predictive enough to assume pathogenicity. 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.

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