rs41341748
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1BS1_SupportingBS2
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
Consequence
NM_138715.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00845 AC: 1283AN: 151830Hom.: 13 Cov.: 32
GnomAD3 exomes AF: 0.00829 AC: 2078AN: 250570Hom.: 22 AF XY: 0.00831 AC XY: 1126AN XY: 135424
GnomAD4 exome AF: 0.00997 AC: 14556AN: 1459882Hom.: 137 Cov.: 31 AF XY: 0.00984 AC XY: 7144AN XY: 726302
GnomAD4 genome AF: 0.00844 AC: 1282AN: 151946Hom.: 13 Cov.: 32 AF XY: 0.00838 AC XY: 622AN XY: 74264
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
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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. -
MSR1: BS1, BS2 -
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. -
Malignant tumor of prostate Uncertain:2
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Hereditary cancer-predisposing syndrome Pathogenic:1
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Barrett esophagus Uncertain:1
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MSR1-related disorder Benign:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at