ClinVar Miner

Submissions for variant NM_000038.6(APC):c.730-3C>T (rs786203125)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166294 SCV000217077 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000412218 SCV000488976 uncertain significance Familial adenomatous polyposis 1 2016-07-28 criteria provided, single submitter clinical testing
Invitae RCV000412218 SCV000552610 uncertain significance Familial adenomatous polyposis 1 2018-05-14 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 186663). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000588450 SCV000566786 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing This variant is denoted APC c.730-3C>T or IVS7-3C>T and consists of a C>T nucleotide substitution at the -3 position of intron 7 of the APC gene. Multiple in silico models predict this variant to weaken the nearby natural acceptor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC c.730-3C>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The cytosine (C) nucleotide that is altered is conserved through mammals. Based on currently available information, it is unclear whether APC c.730-3C>T is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000166294 SCV000687120 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588450 SCV000694113 uncertain significance not provided 2017-02-03 criteria provided, single submitter clinical testing Variant summary: The APC c.730-3C>T variant involves the alteration of a conserved intronic nucleotide. MutationTaster predicts a damaging outcome for this variant. 5/5 splice prediction tools suggest some alteration to normal splicing. ESEfinder also predicts alteration of binding for ESE site(s). Another nucleotide change at the same position, c.730-3C>G, is reported to cause complete loss of exon 7 by in vitro RT-PCR assay (UMD and PMID: 24599579). Therefore this variant is also inferred to cause aberrant splicing but this has yet to be confirmed by functional studies. This variant is absent in 116740 control chromosomes from ExAC. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however has been reported at least to two individuals by clinical labs in ClinVar without details about clinical diagnosis, cosegregation or co-occurrence. An internal sample carrying this variant also carries another variant of uncertain significance ATM p.Lys224Asn. Based on the current available information, though the variant appears to have a possible clinical significance there is no strong supportive evidence. Therefore, this variant is classified as a variant of uncertain significance (VUS), until additional information becomes available.

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