Submissions for variant NM_000321.3(RB1):c.395T>A (p.Phe132Tyr)

gnomAD frequency: 0.00001  dbSNP: rs762380973

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001021530	SCV001183157	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-30	criteria provided, single submitter	clinical testing	The p.F132Y variant (also known as c.395T>A), located in coding exon 4 of the RB1 gene, results from a T to A substitution at nucleotide position 395. The phenylalanine at codon 132 is replaced by tyrosine, an amino acid with highly similar properties. This alteration was identified in 0/1358 non-cancer control individuals and in 1/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035290	SCV001198614	uncertain significance	Retinoblastoma	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 132 of the RB1 protein (p.Phe132Tyr). This variant is present in population databases (rs762380973, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 824431). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function with a negative predictive value of 80%. 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.
All of Us Research Program, National Institutes of Health	RCV001035290	SCV004847092	uncertain significance	Retinoblastoma	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with tyrosine at codon 132 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.