ClinVar Miner

Submissions for variant NM_000321.2(RB1):c.1421G>T (p.Ser474Ile) (rs1555286575)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589809 SCV000696567 likely pathogenic Hereditary cancer-predisposing syndrome 2017-01-24 criteria provided, single submitter clinical testing Variant summary: The RB1 c.1421G>T (p.Ser474Ile) variant involves the alteration of a highly conserved nucleotide and is predicted to be damaging by 5/5 in silico tools. This variant is present at the last nucleotide of exon 15 and is predicted to abrogate or attenuate the splice donor-site by 4/5 splice prediction tools (corroborates ACMG PP3 rule). This variant is located in the Retinoblastoma associated protein, A-box (InterPro). Another nucleotide change at the same cDNA position, c.1421G>A is a pathogenic variant that leads to altered splicing (skipping of exon 15) (see LOVD and PMID: 18181215). Therefore, it is likely that this variant also causes skipping of exon 15. This variant is absent in 24618 control chromosomes from ExAC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. This variant has been reported as a germline variant in one retinoblastoma patient (unpublished finding in LOVD) and as somatic variant in one pancreatic carcinoma patient (unpublished patient in COSMIC). Taken together, this variant is considered as meeting ACMG criteria of Likely Pathogenic (meets PM1, PM2, PM5 and PP3 rules) and hence classified as likely pathogenic.

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