ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2785C>T (p.Arg929Ter) (rs551060742)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000708848 SCV000107577 uncertain significance Lynch syndrome 2019-06-21 reviewed by expert panel curation Nonsense variant after codon 888 in MSH2 = VUS
Invitae RCV001081865 SCV000166279 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-11 criteria provided, single submitter clinical testing
GeneDx RCV000586820 SCV000292728 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2785C>T at the cDNA level and p.Arg929Ter (R929X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). Pinto et al. (2016) reported MSH2 Arg929Ter to co-occur with a nonsense MSH6 variant in eight unrelated Portuguese Lynch syndrome families, suggesting the two variants were present on the same chromosome (in cis). MSH2 and MSH6 are clustered on chromosome 2. Tumor immunohistochemistry (IHC) revealed normal MSH2 expression in 5/8 cases and absence of MSH6 protein in 7/7 cases with interpretable data. In a ninth family in this report, MSH2 Arg929Ter was observed without the MSH6 truncating variant in an individual with colorectal cancer and no family history of cancer. This variant has also been reported in two individuals with colorectal cancer, co-occurring with a pathogenic MSH2 founder pathogenic variant in one individual (Parc 2003, Valentin 2011). Lastly, this variant has been observed in individuals with breast and/or ovarian cancer (Pennington 2014, Lin 2016, Sun 2017). This variant is in the last exon of the gene and is expected to cause loss of the last 6 amino acids. However, due to the location of the newly created nonsense codon in the last exon, the transcript is not expected to undergo nonsense-mediated RNA decay and could therefore encode a truncated protein that retains some normal function. MSH2 Arg929Ter was observed at an allele frequency of 0.10% (19/18,812) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Based on currently available evidence, we consider MSH2 Arg929Ter to be a variant of uncertain significance.
Counsyl RCV000410460 SCV000489175 uncertain significance Lynch syndrome I 2016-08-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000487485 SCV000574719 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-03 criteria provided, single submitter clinical testing The p.R929* variant (also known as c.2785C>T), located in coding exon 16 of the MSH2 gene, results from a C to T substitution at nucleotide position 2785. This changes the amino acid from an arginine to a stop codon within coding exon 16. This alteration has previously been reported in individuals diagnosed with Lynch syndrome; however, several of these individuals carry this alteration in cis with an MSH2 c.942+3A>T mutation (Parc Y et al. J. Med. Genet. 2003 Mar;40(3):208-13; Valentin MD et al. Fam. Cancer. 2011 Dec;10(4):641-7; Ambry internal data). This alteration has also been reported in cis with an MSH6 p.Q344* mutation in eight individuals with Lynch syndrome, and once with only this alteration in a individual diagnosed with colorectal cancer at 36 and no family history of cancer. Tumor results for five of the eight individuals with co-occurrence of the MSH6 p.Q344* mutation had normal MSH2 protein expression on IHC; however, MSH6 protein expression was absent in all available cases (Pinto C et al. J. Hum. Genet. 2016 Feb;61(2):151-6). Furthermore, this alteration has been detected in numerous individuals with no personal or family history of Lynch syndrome (Pennington KP et al. Clin Cancer Res. 2014 Feb 1;20(3):764-75; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Feliubadalo L et al. Sci Rep. 2017 Jan 4;7:37984; Sun J et al. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119; Ambry internal data). This alteration has also been detected in conjunction with a BRCA2 pathogenic mutation in a breast cancer patient (Li JY et al. Int. J. Cancer, 2019 Jan;144:281-289). This alteration occurs at the 3' terminus of the MSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 6 amino acids of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586820 SCV000601470 likely benign not provided 2020-04-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000487485 SCV000685073 likely benign Hereditary cancer-predisposing syndrome 2020-05-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586820 SCV000696256 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2785C>T (p.Arg929X) variant results in a premature termination codon in the final 3 part of the gene, encoding a protein that is 6 AA shorter and without interruption of any known functional domain (Pinto_JHG_2016). One in silico tool predicts a damaging outcome for this variant. This variant was found in 9/114040 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.001065 (9/8454) in ExAC. This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this might be a benign polymorphism found primarily in the populations of East Asian origin. Also, this variant was reported in multiple studies in patients with LS as co-occurring with pathogenic variants MSH2, c. 942+3A>T and MSH6 c.1030C>T, p.Gln344Ter (Valentin_Fam Cancer_2011, Pinto_JHG_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, with one classifying it as likely benign. MSH2 and MSH6 are both on chromosome 2 and it can be inferred the two mutations are in cis and transmitted together (Pinto_JHG_2016), however this variant could confer an increased risk for disease and/or contribute to the mechanism of disease when another pathogenic mutation is present. Considering these conflicting evidence, this variant is classified as a VUS until functional data becomes available.
Mendelics RCV000708848 SCV000837860 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000410460 SCV001135765 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236645 SCV000592556 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The p.Arg989X variant was identified in 10 of 474 proband chromosomes (frequency: 0.021) from South American and Portugese individuals or families with Lynch syndrome, meeting Amsterdam or Bethesda criteria, and was not identified in 200 control chromosomes from healthy individuals (Valentin 2011, Pinto 2015). However eight of the nine patients identified by Pinto et al. were also found to have a co-occurring pathogenic MSH6 mutation (c.1030C>T, p.Gln344X), five of the eight double mutant tumors had normal MSH2 expression and the ninth patient lacked a family history of colon cancer. The patient identified by Valentin et al. was also found to have a co-occurring pathogenic mutation, MSH2: c.942+3A>T (Valentin 2011). The variant was also identified in dbSNP (ID: rs551060742) “With pathogenic allele”, 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 9 of 113840 chromosomes (frequency: 0.00008) (or 9 individuals from a population of 8454 East Asian individuals, frequency 0.001); Clinvitae database (classification pathogenic), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic, and reviewed by an expert panel; being classified as pathogenic by InSight, and uncertain significance by Invitae), and UMD (9x with a “causal” classification). The above classifications were only updated as recently as 2014. The variant was also identified by our laboratory in 1 individual of Portugese background, with colon cancer, co-occurring with a pathogenic MSH6 mutation (c.1030C>T, p.Gln344X), as seen in the Portugese families from Pinto’s study (Pinto_2015_26446363). The p.Arg989X variant leads to a premature stop codon at position 989, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. However, the p.Arg989X encodes a protein 6 amino acids short of the wildtype transcript, without interruption of any known functional domain. Notably, this mutation occurs in the last exon of the MSH2 gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. However, due to conflicting interpretations above, this variant is classified as a variant of unknown significance.

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