ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2120G>A (p.Cys707Tyr)
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.
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.
Uncertain significance(2); Benign(5); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.2120G>A (p.Cys707Tyr)
Variation ID: 182571 Accession: VCV000182571.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47476481 (GRCh38) [ NCBI UCSC ] 2: 47703620 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 6, 2017 May 1, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.2120G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Cys707Tyr missense NM_001258281.1:c.1922G>A NP_001245210.1:p.Cys641Tyr missense NC_000002.12:g.47476481G>A NC_000002.11:g.47703620G>A NG_007110.2:g.78358G>A LRG_218:g.78358G>A LRG_218t1:c.2120G>A LRG_218p1:p.Cys707Tyr - Protein change
- C707Y, C641Y
- Other names
- p.C707Y:TGC>TAC
- Canonical SPDI
- NC_000002.12:47476480:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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 | ||
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HI score
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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. |
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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7401 | 7563 |
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. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 30, 2023 | RCV000160602.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 20, 2023 | RCV000410402.5 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Nov 2, 2021 | RCV000491763.7 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2023 | RCV000761096.6 | |
Benign (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV001085231.9 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV001193853.3 | |
Likely benign (1) |
no assertion criteria provided
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- | RCV001354130.3 |
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. |
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Likely benign
(Feb 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000580507.6
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Jun 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000902862.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
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Likely benign
(Nov 02, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002534448.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Mar 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018292.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features … (more)
This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Benign
(Aug 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134351.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
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Benign
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000559226.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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Likely Benign
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004827829.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Number of individuals with the variant: 11
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Benign
(Feb 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363001.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MSH2 c.2120G>A (p.Cys707Tyr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded … (more)
Variant summary: MSH2 c.2120G>A (p.Cys707Tyr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 277212 control chromosomes, predominantly at a frequency of 0.0033 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.2120G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x) and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Dec 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000891011.2
First in ClinVar: Mar 19, 2019 Last updated: Dec 17, 2020 |
Comment:
The MSH2 c.2120G>A (p.Cys707Tyr) missense change has a maximum subpopulation frequency of 0.33% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47703620-G-A). This population frequency is higher than expected for … (more)
The MSH2 c.2120G>A (p.Cys707Tyr) missense change has a maximum subpopulation frequency of 0.33% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47703620-G-A). This population frequency is higher than expected for a pathogenic variant in MSH2 causing Lynch syndrome (BS1). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. A case control study of MSH2 variants identified the p.C707Y variant in 1.4% of cases with colorectal cancer and/or suspected Lynch syndrome and in 2% of healthy controls (BS2_Supporting, PMID: 31660093). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BS2_Supporting, PP3. (less)
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Uncertain significance
(Jul 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211198.14
First in ClinVar: Feb 24, 2015 Last updated: Dec 17, 2022 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome-associated tumors and other cancers, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome-associated tumors and other cancers, but also in unaffected controls (Rashid et al., 2019; Ryan et al., 2020; Aswath et al., 2021); This variant is associated with the following publications: (PMID: 30122538, 31660093, 32941469, 34426522, 21120944, 18822302, 35415788, 34326811) (less)
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Uncertain significance
(Jan 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488196.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024762.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548671.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Cys707Tyr variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs373226409) … (more)
The MSH2 p.Cys707Tyr variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs373226409) as “with uncertain significance allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics and Color; and as uncertain significance by GeneDx, Counsyl and one other submitter). The variant was identified in control databases in 109 of 277,212 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 101 of 30,782 chromosomes (freq: 0.003, increasing the likelihood this could be a low frequency benign variant) and European in 8 of 126,714 chromosomes (freq: 0.00006); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian or Finnish populations. The variant was identified by our laboratory as co-occurring with a pathogenic variant in MLH1 (p.Ser44Phe). The p.Cys707 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. This variant is classified as likely benign. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study. | Nassar A | Genes | 2022 | PMID: 36672847 |
Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. | Bhai P | Frontiers in genetics | 2021 | PMID: 34326862 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients. | Rashid MU | Hereditary cancer in clinical practice | 2019 | PMID: 31660093 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Text-mined citations for rs373226409 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.