NM_000321.3(RB1):c.1573G>A (p.Ala525Thr) AND Retinoblastoma

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 11, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000701091.16

Allele description [Variation Report for NM_000321.3(RB1):c.1573G>A (p.Ala525Thr)]

NM_000321.3(RB1):c.1573G>A (p.Ala525Thr)

Gene:

RB1:RB transcriptional corepressor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.2

Genomic location:

Preferred name:

NM_000321.3(RB1):c.1573G>A (p.Ala525Thr)

HGVS:

NC_000013.11:g.48381321G>A
NG_009009.1:g.82575G>A
NM_000321.3:c.1573G>AMANE SELECT
NP_000312.2:p.Ala525Thr
NP_000312.2:p.Ala525Thr
LRG_517t1:c.1573G>A
LRG_517:g.82575G>A
LRG_517p1:p.Ala525Thr
NC_000013.10:g.48955457G>A
NM_000321.2:c.1573G>A

Protein change:

A525T

Links:

dbSNP: rs587778640

NCBI 1000 Genomes Browser:

rs587778640

Molecular consequence:

NM_000321.3:c.1573G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Retinoblastoma (RB1)
Synonyms:: Eye cancer, retinoblastoma; RETINOBLASTOMA, SOMATIC
Identifiers:: MONDO: MONDO:0008380; MeSH: D012175; MedGen: C0035335; Orphanet: 790; OMIM: 180200; Human Phenotype Ontology: HP:0009919

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000829874	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Oct 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001268039	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV004844682	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24728327, 34680218, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000829874

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Benign
(Oct 26, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001268039

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Likely benign
(Jan 12, 2018)

germline

clinical testing

Citation Link,

SCV004844682

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]

PMID:: 24728327
PMCID:: PMC3984285

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000829874.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001268039.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004844682.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces alanine with threonine at codon 525 of the RB1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with unilateral retinoblastoma but was also found in their unaffected parent and in other asymptomatic individuals (PMID: 24728327, 34680218). This variant has been identified in 15/249180 chromosomes in the general population by the Genome Aggregation Database (gnomAD), suggesting the variant frequency is greater than expected for the disease. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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