Submissions for variant NM_000321.3(RB1):c.628G>T (p.Asp210Tyr)

gnomAD frequency: 0.00009  dbSNP: rs148992508

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492290	SCV000580788	likely benign	Hereditary cancer-predisposing syndrome	2020-08-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079302	SCV000629339	benign	Retinoblastoma	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000601517	SCV000714123	likely benign	not specified	2018-02-15	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.
Illumina Laboratory Services, Illumina	RCV001079302	SCV001271625	likely benign	Retinoblastoma	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000601517	SCV002050810	likely benign	not specified	2021-12-07	criteria provided, single submitter	clinical testing	Variant summary: RB1 c.628G>T (p.Asp210Tyr) results in a non-conservative amino acid change located in the Retinoblastoma-associated protein, N-terminal domain (IPR024599) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250442 control chromosomes, predominantly at a frequency of 0.0038 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 91-fold of the estimated maximal expected allele frequency for a pathogenic variant in RB1 causing Retinoblastoma phenotype (4.2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.628G>T has been reported in the literature as a secondary finding in a study of cancer susceptibility genes in individuals affected with atherosclerosis (Johnston_2012). This report does not provide conclusions about association of the variant with Retinoblastoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: three have classified the variant as likely benign and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000492290	SCV002530861	likely benign	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034597	SCV004133123	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001079302	SCV004357198	benign	Retinoblastoma	2022-04-26	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034597	SCV000043464	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.