ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.2437C>T (p.Arg813Trp)
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(8); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.2437C>T (p.Arg813Trp)
Variation ID: 127783 Accession: VCV000127783.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5977596 (GRCh38) [ NCBI UCSC ] 7: 6017227 (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 Jun 1, 2016 May 1, 2024 Jan 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.2437C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Arg813Trp missense NM_001322003.2:c.2032C>T NP_001308932.1:p.Arg678Trp missense NM_001322004.2:c.2032C>T NP_001308933.1:p.Arg678Trp missense NM_001322005.2:c.2032C>T NP_001308934.1:p.Arg678Trp missense NM_001322006.2:c.2281C>T NP_001308935.1:p.Arg761Trp missense NM_001322007.2:c.2119C>T NP_001308936.1:p.Arg707Trp missense NM_001322008.2:c.2119C>T NP_001308937.1:p.Arg707Trp missense NM_001322009.2:c.2065C>T NP_001308938.1:p.Arg689Trp missense NM_001322010.2:c.1876C>T NP_001308939.1:p.Arg626Trp missense NM_001322011.2:c.1504C>T NP_001308940.1:p.Arg502Trp missense NM_001322012.2:c.1504C>T NP_001308941.1:p.Arg502Trp missense NM_001322013.2:c.1864C>T NP_001308942.1:p.Arg622Trp missense NM_001322014.2:c.2470C>T NP_001308943.1:p.Arg824Trp missense NM_001322015.2:c.2128C>T NP_001308944.1:p.Arg710Trp missense NR_136154.1:n.2481C>T non-coding transcript variant NC_000007.14:g.5977596G>A NC_000007.13:g.6017227G>A NG_008466.1:g.36511C>T LRG_161:g.36511C>T LRG_161t1:c.2437C>T - Protein change
- R813W, R626W, R502W, R678W, R707W, R622W, R689W, R761W, R824W, R710W
- Other names
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- Canonical SPDI
- NC_000007.14:5977595: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00011
The Genome Aggregation Database (gnomAD) 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00023
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00029
1000 Genomes Project 30x 0.00031
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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PMS2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5155 | 5249 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 10, 2024 | RCV000115687.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 9, 2024 | RCV000196074.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 6, 2023 | RCV000212874.9 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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May 22, 2023 | RCV000656952.10 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Dec 4, 2023 | RCV003153372.3 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 23, 2024 | RCV003492487.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 18, 2023 | RCV003467055.1 |
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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Uncertain significance
(Oct 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004205375.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(May 22, 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: SCV000888409.4
First in ClinVar: Jul 09, 2018 Last updated: Jan 06, 2024 |
Comment:
In the published literature, the variant has been reported in individuals with a personal or family history of colorectal cancer (PMID: 26900293 (2016), 33413596 (2021)) … (more)
In the published literature, the variant has been reported in individuals with a personal or family history of colorectal cancer (PMID: 26900293 (2016), 33413596 (2021)) and breast cancer (PMID: 35449176 (2022), 36200007 (2022)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (see LOVD (http://databases.lovd.nl/shared/genes/PMS2) and PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.00035 (6/17216 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Nov 03, 2022)
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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: SCV004358987.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 813 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with tryptophan at codon 813 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 26900293, 34172528). This variant has been identified in 19/201724 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 09, 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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Invitae
Accession: SCV000255293.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 813 of the PMS2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 813 of the PMS2 protein (p.Arg813Trp). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127783). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 10, 2024)
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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: SCV000215363.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.R813W variant (also known as c.2437C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide … (more)
The p.R813W variant (also known as c.2437C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide position 2437. The arginine at codon 813 is replaced by tryptophan, an amino acid with dissimilar properties. One study detected this alteration in 1/103 Taiwanese colorectal cancer patients (Chang YC et al. World J. Gastroenterol., 2016 Feb;22:2314-25). This alteration has also been reported in a cohort of 235 new female breast caner patients from India (Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Oct 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000596464.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
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Uncertain significance
(Jul 20, 2018)
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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: SCV000149596.14
First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted PMS2 c.2437C>T at the cDNA level, p.Arg813Trp (R813W) at the protein level, and results in the change of an Arginine to … (more)
This variant is denoted PMS2 c.2437C>T at the cDNA level, p.Arg813Trp (R813W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located in a zinc binding motif in the endonuclease domain (Kosinski 2008, Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Arg813Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Nov 06, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918043.3
First in ClinVar: Jun 02, 2019 Last updated: Jan 06, 2024 |
Comment:
Variant summary: PMS2 c.2437C>T (p.Arg813Trp) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. … (more)
Variant summary: PMS2 c.2437C>T (p.Arg813Trp) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) 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 6.1e-05 in 1558782 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (6.1e-05 vs 7.1e-05), allowing no conclusion about variant significance. Additionally, this allele frequency needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured. c.2437C>T has been reported in the literature in individuals affected with Colorectal Cancer (Chang_2016), therapy-related myeloid neoplasms (Singhal_2021), gastric cancer (Zhang_2021), and breast cancer (Hu_2022, Mittal_2022), however without strong evidence for causality (e.g., lack of co-segregation data). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26900293, 33413596, 35449176, 33850299, 34567566, 36200007). Six submitters have reported this variant to ClinVar after 2014 with conflicting assessments (uncertain significance, n = 5; likely pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV004232573.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951603.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742269.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(Jan 01, 2022)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Ovarian cancer
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University
Accession: SCV003843798.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Spectrum and management of breast cancer patients with variant of uncertain significance mutations at a tertiary care centre in North India. | Mittal A | Ecancermedicalscience | 2022 | PMID: 36200007 |
Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients. | Hu L | NPJ breast cancer | 2022 | PMID: 35449176 |
Prevalence and spectrum of DNA mismatch repair gene variation in the general Chinese population. | Zhang L | Journal of medical genetics | 2022 | PMID: 34172528 |
A multicenter study assessing the prevalence of germline genetic alterations in Chinese gastric-cancer patients. | Zhang YJ | Gastroenterology report | 2021 | PMID: 34567566 |
Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer. | Singhal D | Leukemia | 2021 | PMID: 33850299 |
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 |
Family history assessment significantly enhances delivery of precision medicine in the genomics era. | Bylstra Y | Genome medicine | 2021 | PMID: 33413596 |
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry. | Matejcic M | JCO precision oncology | 2020 | PMID: 32832836 |
Variants of DNA mismatch repair genes derived from 33,998 Chinese individuals with and without cancer reveal their highly ethnic-specific nature. | Zhang L | European journal of cancer (Oxford, England : 1990) | 2020 | PMID: 31830689 |
Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients. | Chang YC | World journal of gastroenterology | 2016 | PMID: 26900293 |
Text-mined citations for rs375968016 ...
HelpRecord last updated May 08, 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.