ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.2395C>T (p.Arg799Trp)
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(5); Benign(1); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.2395C>T (p.Arg799Trp)
Variation ID: 91340 Accession: VCV000091340.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5977638 (GRCh38) [ NCBI UCSC ] 7: 6017269 (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 Mar 24, 2015 Oct 8, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.2395C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Arg799Trp missense NM_001322003.2:c.1990C>T NP_001308932.1:p.Arg664Trp missense NM_001322004.2:c.1990C>T NP_001308933.1:p.Arg664Trp missense NM_001322005.2:c.1990C>T NP_001308934.1:p.Arg664Trp missense NM_001322006.2:c.2239C>T NP_001308935.1:p.Arg747Trp missense NM_001322007.2:c.2077C>T NP_001308936.1:p.Arg693Trp missense NM_001322008.2:c.2077C>T NP_001308937.1:p.Arg693Trp missense NM_001322009.2:c.2023C>T NP_001308938.1:p.Arg675Trp missense NM_001322010.2:c.1834C>T NP_001308939.1:p.Arg612Trp missense NM_001322011.2:c.1462C>T NP_001308940.1:p.Arg488Trp missense NM_001322012.2:c.1462C>T NP_001308941.1:p.Arg488Trp missense NM_001322013.2:c.1822C>T NP_001308942.1:p.Arg608Trp missense NM_001322014.2:c.2428C>T NP_001308943.1:p.Arg810Trp missense NM_001322015.2:c.2086C>T NP_001308944.1:p.Arg696Trp missense NR_136154.1:n.2439C>T non-coding transcript variant NC_000007.14:g.5977638G>A NC_000007.13:g.6017269G>A NG_008466.1:g.36469C>T LRG_161:g.36469C>T LRG_161t1:c.2395C>T - Protein change
- R799W, R612W, R664W, R696W, R810W, R488W, R608W, R675W, R693W, R747W
- Other names
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- Canonical SPDI
- NC_000007.14:5977637: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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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00026
The Genome Aggregation Database (gnomAD), exomes 0.00051
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00056
1000 Genomes Project 0.00080
1000 Genomes Project 30x 0.00094
Trans-Omics for Precision Medicine (TOPMed) 0.00123
The Genome Aggregation Database (gnomAD) 0.00142
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
Help
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 |
5239 | 5341 |
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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Dec 19, 2022 | RCV000162455.7 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jul 31, 2024 | RCV000215298.14 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV000524466.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 7, 2023 | RCV000590372.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000764720.3 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Oct 24, 2023 | RCV003153358.3 | |
PMS2-related disorder
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Likely benign (1) |
no assertion criteria provided
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May 16, 2024 | RCV004742245.1 |
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
(May 04, 2022)
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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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Mendelics
Accession: SCV002519144.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Uncertain significance
(Dec 19, 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: SCV004358995.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 799 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 799 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 Lynch syndrome or Lynch syndrome-associated cancers (PMID: 24072394, 28135145, 28449805), breast/ovarian cancer (PMID: 28528518, 31921681 33471991), or pancreatic cancer (PMID: 26483394) This variant has been identified in 119/233620 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in multiple healthy control individuals (PMID: 33471991). This observed population allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. 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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Likely benign
(Dec 13, 2018)
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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: SCV000212809.7
First in ClinVar: Mar 24, 2015 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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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Mismatch repair cancer syndrome 1
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895855.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely benign
(Jun 02, 2021)
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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: SCV000279151.9
First in ClinVar: May 29, 2016 Last updated: Mar 17, 2018 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of Lynch syndrome-related cancers, at least one of whom had tumor studies consistent with pathogenic variants in this gene (Zahary 2014, Hu 2016, Sunga 2017, Yurgelun 2017, Cock-Rada 2018, Oliver 2019, Li 2020); This variant is associated with the following publications: (PMID: 24072394, 26483394, 26798439, 28135145, 26333163, 28528518, 30979843, 30122538, 31391288, 31921681, 28449805) (less)
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Uncertain significance
(Dec 20, 2021)
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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: SCV002070520.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
Comment:
DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2395C>T, in exon 14 that results in an amino acid change, p.Arg799Trp. This sequence … (more)
DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2395C>T, in exon 14 that results in an amino acid change, p.Arg799Trp. This sequence change has been described in the gnomAD database with a frequency of 0.31% in the Latino/Admixed American subpopulation including one homozygous individual (dbSNP rs149202766). The p.Arg799Trp change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Arg799Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been identified in individuals evaluated for Lynch syndrome, in an individual with pancreatic adenocarcinoma, and in individuals assessed for hereditary breast and ovarian cancer (PMID: 28449805, 28528518, 24072394, 2648339). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg799Trp change remains unknown at this time. (less)
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Likely benign
(Oct 02, 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: SCV000697346.4
First in ClinVar: Mar 17, 2018 Last updated: Nov 20, 2023 |
Comment:
Variant summary: PMS2 c.2395C>T (p.Arg799Trp) 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.2395C>T (p.Arg799Trp) 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 0.00051 in 238072 control chromosomes, predominantly at a frequency of 0.0031 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. Furthermore, the variant allele was found at a frequency of 0.001391 in 149538 control chromosomes, predominantly at a frequency of 0.01181 within the Latino subpopulation in the gnomAD (v3) database, including 9 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD (v3) database is approximately 107-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. This observation needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured, although the observation of at least 9 homozygotes, decreases the likelihood of a pseudogene artefact. c.2395C>T has been reported in the literature in sequencing studies of individuals affected with pancreatic cancer, Lynch Syndrome and hereditary breast and ovarian cancer syndrome (e.g. Cock-Rada_2017, Hu_2016, Li_2020, Oliver_2019, Sunga_2017, Yurgelun_2017, Zahary_2014). Specifically, Zahary_2014 reports the variant in one suspected Lynch syndrome patient who was indicated to have absent PMS2 protein expression, although the IHC findings from MLH1 and MSH2 were not provided. Furthermore, co-occurrence and cosegregation data and MLH1 gene testing results were not reported. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in a HBOC patient (BRCA1 c.1674delA, p.Gly559fsX13; Cock-Rada_2017), providing additional supporting evidence for a non-pathogenic role attributed to this variant. The following publications have been ascertained in the context of this evaluation (PMID: 26483394, 26333163, 24072394, 28135145, 28528518, 28449805, 30122538, 31391288, 31921681, 35449176). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4), likely benign (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Sep 07, 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: SCV000888408.5
First in ClinVar: Mar 17, 2018 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs:35449176 (2022), 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2, 31921681 (2019), 28528518 (2017)), … (more)
In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs:35449176 (2022), 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2, 31921681 (2019), 28528518 (2017)), colorectal cancer (PMIDs: 28135145 (2017), 28449805 (2017), 24072394 (2014)), and pancreatic cancer (PMID: 26483394 (2015)), as well as in unaffected individuals in a large breast cancer association study (PMIDs: 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2). The frequency of this variant in the general population, 0.0031 (108/34802 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely benign
(Jan 30, 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: SCV000552023.9
First in ClinVar: Mar 24, 2015 Last updated: Feb 14, 2024 |
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Benign
(Jul 31, 2024)
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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: SCV005090725.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
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Likely benign
(May 16, 2024)
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no assertion criteria provided
Method: clinical testing
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PMS2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005352174.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
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).
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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: SCV003843752.1
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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Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients. | Hu L | NPJ breast cancer | 2022 | PMID: 35449176 |
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 |
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach. | Oliver J | Frontiers in oncology | 2019 | PMID: 31921681 |
Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot. | Sapp JC | American journal of human genetics | 2018 | PMID: 30122538 |
A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. | Cock-Rada AM | Familial cancer | 2018 | PMID: 28528518 |
Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome. | Sunga AY | Cancer genetics | 2017 | PMID: 28449805 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes. | Dobbins SE | Familial cancer | 2016 | PMID: 27356891 |
Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer. | Tezcan G | World journal of gastrointestinal oncology | 2016 | PMID: 26798439 |
Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. | Hu C | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2016 | PMID: 26483394 |
Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2. | Niroula A | Human mutation | 2015 | PMID: 26333163 |
Germline mutation and protein expression analysis of mismatch repair genes MSH6 and PMS2 in Malaysian Lynch syndrome patients. | Zahary MN | International journal of colorectal disease | 2014 | PMID: 24072394 |
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Text-mined citations for rs149202766 ...
HelpRecord last updated Oct 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.