NM_138715.3:c.877C>T

Variant names:

• chr8-16155085-G-A
• rs41341748
• NM_138715.3:c.877C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_138715.3(MSR1):​c.877C>T​(p.Arg293*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00983 in 1,611,828 control chromosomes in the GnomAD database, including 150 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0084 (13 hom., cov: 32)
  • Exomes 𝑓: 0.010 (137 hom.)
• Consequence: MSR1 NM_138715.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:4
• Conservation: PhyloP100: 1.22
• Publications: 66 publications found

Genes affected

MSR1 (HGNC:7376): (macrophage scavenger receptor 1) This gene encodes the class A macrophage scavenger receptors, which include three different types (1, 2, 3) generated by alternative splicing of this gene. These receptors or isoforms are macrophage-specific trimeric integral membrane glycoproteins and have been implicated in many macrophage-associated physiological and pathological processes including atherosclerosis, Alzheimer's disease, and host defense. The isoforms type 1 and type 2 are functional receptors and are able to mediate the endocytosis of modified low density lipoproteins (LDLs). The isoform type 3 does not internalize modified LDL (acetyl-LDL) despite having the domain shown to mediate this function in the types 1 and 2 isoforms. It has an altered intracellular processing and is trapped within the endoplasmic reticulum, making it unable to perform endocytosis. The isoform type 3 can inhibit the function of isoforms type 1 and type 2 when co-expressed, indicating a dominant negative effect and suggesting a mechanism for regulation of scavenger receptor activity in macrophages. [provided by RefSeq, Jul 2008]

MSR1 Gene-Disease associations (from GenCC):

• Barrett esophagus

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 8-16155085-G-A is Benign according to our data. Variant chr8-16155085-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14357.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00844 (1282/151946) while in subpopulation AMR AF = 0.0131 (200/15214). AF 95% confidence interval is 0.0117. There are 13 homozygotes in GnomAd4. There are 622 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSR1	NM_138715.3	c.877C>T	p.Arg293*	stop_gained	Exon 6 of 10	ENST00000262101.10	NP_619729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSR1	ENST00000262101.10	c.877C>T	p.Arg293*	stop_gained	Exon 6 of 10	1	NM_138715.3	ENSP00000262101.5

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1283 AN: 151830 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0130

GnomAD2 exomes AF: 0.00829 AC: 2078 AN: 250570 AF XY: 0.00831

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00926

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00997 AC: 14556 AN: 1459882 Hom.: 137 Cov.: 31 AF XY: 0.00984 AC XY: 7144 AN XY: 726302

African (AFR) AF: 0.00177 AC: 59 AN: 33406

American (AMR) AF: 0.0117 AC: 523 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 365 AN: 26052

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39664

South Asian (SAS) AF: 0.000870 AC: 75 AN: 86218

European-Finnish (FIN) AF: 0.00935 AC: 499 AN: 53344

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5758

European-Non Finnish (NFE) AF: 0.0112 AC: 12389 AN: 1110594

Other (OTH) AF: 0.0102 AC: 613 AN: 60264

GnomAD4 genome AF: 0.00844 AC: 1282 AN: 151946 Hom.: 13 Cov.: 32 AF XY: 0.00838 AC XY: 622 AN XY: 74264

African (AFR) AF: 0.00217 AC: 90 AN: 41492

American (AMR) AF: 0.0131 AC: 200 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3466

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0117 AC: 124 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0117 AC: 794 AN: 67898

Other (OTH) AF: 0.0128 AC: 27 AN: 2104

Alfa AF: 0.0102 Hom.: 37

Bravo AF: 0.00835

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00735 AC: 892

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.00979

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSR1: BS1, BS2 -

Mar 23, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Prostate cancer Uncertain:2

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2011

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 07, 2015

Vantari Genetics

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Barrett esophagus Uncertain:1

Jul 23, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSR1-related disorder Benign:1

Oct 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

X-linked Alport syndrome Benign:1

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.076	N
PhyloP100		1.2
Vest4		0.73
GERP RS		2.8
Mutation Taster		=179/21	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41341748; hg19: chr8-16012594; COSMIC: COSV50509521;