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

dbSNP: rs41341748

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481066	SCV000565244	uncertain significance	not provided	2017-03-23	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000481066	SCV001097461	benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000015431	SCV001137589	uncertain significance	Malignant tumor of prostate	2019-05-28	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001258304	SCV001435253	likely benign	X-linked Alport syndrome		criteria provided, single submitter	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.
Revvity Omics, Revvity	RCV003133117	SCV003808973	uncertain significance	Barrett esophagus	2019-07-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000481066	SCV004164414	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MSR1: BS1, BS2
OMIM	RCV000015431	SCV000035696	uncertain significance	Malignant tumor of prostate	2011-07-27	no assertion criteria provided	literature only
Vantari Genetics	RCV000210798	SCV000267057	pathogenic	Hereditary cancer-predisposing syndrome	2015-12-07	flagged submission	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000481066	SCV001554441	uncertain significance	not provided		no assertion criteria provided	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.
PreventionGenetics, part of Exact Sciences	RCV003964803	SCV004789972	likely benign	MSR1-related disorder	2019-10-29	no assertion criteria provided	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).