VCV000014357.23 - ClinVar

NM_138715.3(MSR1):c.877C>T (p.Arg293Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(3); Benign(2); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_138715.3(MSR1):c.877C>T (p.Arg293Ter)

Variation ID: 14357 Accession: VCV000014357.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p22 8: 16155085 (GRCh38) [ NCBI UCSC ] 8: 16012594 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 11, 2015	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_138715.3:c.877C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_619729.1:p.Arg293Ter	nonsense
NM_001363744.1:c.931C>T	NP_001350673.1:p.Arg311Ter	nonsense
NM_002445.4:c.877C>T	NP_002436.1:p.Arg293Ter	nonsense
NM_138716.3:c.877C>T	NP_619730.1:p.Arg293Ter	nonsense
NC_000008.11:g.16155085G>A
NC_000008.10:g.16012594G>A
NG_012102.1:g.42707C>T

... more HGVS ... less HGVS

Protein change

R293*, R311*

Other names

Canonical SPDI

NC_000008.11:16155084:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00539 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00531

1000 Genomes Project 0.00539

Trans-Omics for Precision Medicine (TOPMed) 0.00765

Links

OMIM: 153622.0001 dbSNP: rs41341748 ClinGen: CA123891 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MSR1		-	-	GRCh38 GRCh37	78	170

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Malignant tumor of prostate	Uncertain significance (2)	criteria provided, single submitter	May 28, 2019	RCV000015431.24
Hereditary cancer-predisposing syndrome	no classifications from unflagged records (1)	no classifications from unflagged records	Jul 12, 2024	RCV000210798.4
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jul 1, 2024	RCV000481066.21
X-linked Alport syndrome	Likely benign (1)	criteria provided, single submitter	-	RCV001258304.4
Barrett esophagus	Uncertain significance (1)	criteria provided, single submitter	Jul 23, 2019	RCV003133117.5
MSR1-related disorder	Likely benign (1)	no assertion criteria provided	Oct 29, 2019	RCV003964803.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 23, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000565244.4 First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017	Comment: The R293X variant in the MSR1 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This … (more) The R293X variant in the MSR1 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been reported previously in several individuals with a diagnosis of Barrett's esophagus and/or esophageal adenocarcinoma (Orloff et al., 2011); however, specific phenotypic details and familial segregation information were not provided. The R293X variant has also been reported previously in association with prostate cancer in multiple individuals with and without a family history of prostate cancer, although segregation of R293X with cancer was incomplete in several families (Xu et al., 2002; Gonzalez-Garay et al., 2013). In addition, a study assessing the frequency of MSR1 variants in individuals with prostate cancer identified R293X in equal frequency among both familial and sporadic prostate cancer cohorts as well as an equal frequency among healthy controls (Maier et al., 2006). The R293X variant is observed in 890/119706 (0.01%%) alleles in the ExAC dataset, including 13 homozygotes (Lek et al., 2016). We interpret R293X as a variant of uncertain significance. (less)
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Familial prostate cancer Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137589.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Dec 31, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001097461.2 First in ClinVar: Dec 17, 2019 Last updated: May 04, 2020
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	X-linked Alport syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435253.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (4) PubMed: 12244320‚ 25333069‚ 24082139‚ 21791690 Comment: The heterozygous p.Arg293Ter variant in MSR1 has been identified in 8 individuals with prostate cancer and multiple individuals without reported prostate cancer (PMID: 12244320, 21791690, … (more) The heterozygous p.Arg293Ter variant in MSR1 has been identified in 8 individuals with prostate cancer and multiple individuals without reported prostate cancer (PMID: 12244320, 21791690, 24082139, 25333069), but has also been identified in >1% of Latino chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg293Ter variant may slightly impact protein function (PMID: 21791690). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant prostate cancer. (less)
Benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004164414.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: MSR1: BS1, BS2 Number of individuals with the variant: 6
Uncertain significance (Jul 23, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Barrett esophagus Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003808973.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jul 27, 2011)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035696.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015	Publications: PubMed (3) PubMed: 12958598‚ 12244320‚ 21791690 Comment on evidence: This variant, formerly titled PROSTATE CANCER, has been reclassified based on the report of Wang et al. (2003). In 6 different families, all of European … (more) This variant, formerly titled PROSTATE CANCER, has been reclassified based on the report of Wang et al. (2003). In 6 different families, all of European descent, with hereditary prostate cancer (176807), Xu et al. (2002) found a nonsense mutation, arg293 to ter (R293X), in the MSR1 gene. Wang et al. (2003) found no statistical difference between prostate cancer cases with the R293X mutation and controls for either familial or sporadic cancer. Orloff et al. (2011) identified a germline 877C-T transition in the MSR1 gene, resulting in an arg293-to-ter (R293X) substitution in a highly conserved collagen-like domain, in 8 (6.9%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The findings were replicated in an independent study of 58 patients, of whom 2 (3.4%) had the R293X mutation. The mutation was not found in 139 controls. Western blot analysis showed variable decreases in the MSR1 protein in 3 of 5 cases with the mutation, and all 5 patients had increased nuclear expression of cyclin D1 (CCND1; 168461) compared to controls. The findings suggested a link between inflammation and the cell cycle and the development of Barrett esophagus and/or esophageal cancer. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorders. (less)
Likely benign (Oct 29, 2019)	no assertion criteria provided Method: clinical testing	MSR1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004789972.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001554441.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The MSR1 p.R293* variant was identified in 45 of 4502 proband chromosomes (frequency: 0.001) from individuals or families with prostate cancer and 10 of 348 … (more) The MSR1 p.R293* variant was identified in 45 of 4502 proband chromosomes (frequency: 0.001) from individuals or families with prostate cancer and 10 of 348 proband chromosomes (frequency: 0.029) from individuals with Barrett esophagus and esophageal adenocarcinoma, but was also identified in 26 of 2636 control chromosomes (frequency: 0.0099) from healthy individuals (Orloff_2011_PMID:21791690; Xu_2002_PMID:12244320; Wang_2003_PMID:12958598; Maier_2006_PMID:16287155; Seppala_2003_PMID:14614006). An association study of almost 3,000 prostate cancer cases and 2,800 controls did not identify a significant difference in the frequency of R293* in cases compared to controls (Hope_2005_PMID:15734964). The variant was identified in dbSNP (ID: rs41341748), ClinVar (classified as a VUS by GeneDx and as pathogenic by Vantari Genetics) and Cosmic (FATHMM prediction of neutral; score=0.08). The variant was also identified in control databases in 2324 of 281916 chromosomes (23 homozygous) at a frequency of 0.008244 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 155 of 10344 chromosomes (freq: 0.01498), Latino in 413 of 35264 chromosomes (freq: 0.01171), Other in 82 of 7174 chromosomes (freq: 0.01143), European (non-Finnish) in 1370 of 128636 chromosomes (freq: 0.01065), European (Finnish) in 231 of 25070 chromosomes (freq: 0.009214), African in 50 of 24926 chromosomes (freq: 0.002006), South Asian in 22 of 30596 chromosomes (freq: 0.000719), and East Asian in 1 of 19906 chromosomes (freq: 0.00005). The c.877C>T variant leads to a premature stop codon at position 293 which is predicted to lead to a truncated or absent protein and loss of function. The role of loss of function variants of the MSR1 gene in disease is currently unclear. Western blots of the MSR1 protein in patients with Barrett esophagus and esophageal adenocarcinoma carrying the R293* variant showed MSR1 protein expression, although at lower level in some patients (Orloff_2011_PMID:21791690). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
Pathogenic (Dec 07, 2015)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Vantari Genetics Accession: SCV000267057.1 First in ClinVar: Apr 14, 2016 Last updated: Apr 14, 2016
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

The R293X variant in the MSR1 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been reported previously in several individuals with a diagnosis of Barrett's esophagus and/or esophageal adenocarcinoma (Orloff et al., 2011); however, specific phenotypic details and familial segregation information were not provided. The R293X variant has also been reported previously in association with prostate cancer in multiple individuals with and without a family history of prostate cancer, although segregation of R293X with cancer was incomplete in several families (Xu et al., 2002; Gonzalez-Garay et al., 2013). In addition, a study assessing the frequency of MSR1 variants in individuals with prostate cancer identified R293X in equal frequency among both familial and sporadic prostate cancer cohorts as well as an equal frequency among healthy controls (Maier et al., 2006). The R293X variant is observed in 890/119706 (0.01%%) alleles in the ExAC dataset, including 13 homozygotes (Lek et al., 2016). We interpret R293X as a variant of uncertain significance.

Comment:

The heterozygous p.Arg293Ter variant in MSR1 has been identified in 8 individuals with prostate cancer and multiple individuals without reported prostate cancer (PMID: 12244320, 21791690, 24082139, 25333069), but has also been identified in >1% of Latino chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg293Ter variant may slightly impact protein function (PMID: 21791690). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant prostate cancer.

Comment:

The MSR1 p.R293* variant was identified in 45 of 4502 proband chromosomes (frequency: 0.001) from individuals or families with prostate cancer and 10 of 348 proband chromosomes (frequency: 0.029) from individuals with Barrett esophagus and esophageal adenocarcinoma, but was also identified in 26 of 2636 control chromosomes (frequency: 0.0099) from healthy individuals (Orloff_2011_PMID:21791690; Xu_2002_PMID:12244320; Wang_2003_PMID:12958598; Maier_2006_PMID:16287155; Seppala_2003_PMID:14614006). An association study of almost 3,000 prostate cancer cases and 2,800 controls did not identify a significant difference in the frequency of R293* in cases compared to controls (Hope_2005_PMID:15734964). The variant was identified in dbSNP (ID: rs41341748), ClinVar (classified as a VUS by GeneDx and as pathogenic by Vantari Genetics) and Cosmic (FATHMM prediction of neutral; score=0.08). The variant was also identified in control databases in 2324 of 281916 chromosomes (23 homozygous) at a frequency of 0.008244 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 155 of 10344 chromosomes (freq: 0.01498), Latino in 413 of 35264 chromosomes (freq: 0.01171), Other in 82 of 7174 chromosomes (freq: 0.01143), European (non-Finnish) in 1370 of 128636 chromosomes (freq: 0.01065), European (Finnish) in 231 of 25070 chromosomes (freq: 0.009214), African in 50 of 24926 chromosomes (freq: 0.002006), South Asian in 22 of 30596 chromosomes (freq: 0.000719), and East Asian in 1 of 19906 chromosomes (freq: 0.00005). The c.877C>T variant leads to a premature stop codon at position 293 which is predicted to lead to a truncated or absent protein and loss of function. The role of loss of function variants of the MSR1 gene in disease is currently unclear. Western blots of the MSR1 protein in patients with Barrett esophagus and esophageal adenocarcinoma carrying the R293* variant showed MSR1 protein expression, although at lower level in some patients (Orloff_2011_PMID:21791690). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Disease variants in genomes of 44 centenarians.	Freudenberg-Hua Y	Molecular genetics & genomic medicine	2014	PMID: 25333069
Personalized genomic disease risk of volunteers.	Gonzalez-Garay ML	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 24082139
Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma.	Orloff M	JAMA	2011	PMID: 21791690
No association of germline alteration of MSR1 with prostate cancer risk.	Wang L	Nature genetics	2003	PMID: 12958598
Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.	Xu J	Nature genetics	2002	PMID: 12244320

Text-mined citations for rs41341748 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_138715.3(MSR1):c.877C>T (p.Arg293Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs41341748 ...