ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.2347G>A (p.Val783Ile)
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(10); 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.2347G>A (p.Val783Ile)
Variation ID: 185820 Accession: VCV000185820.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5977686 (GRCh38) [ NCBI UCSC ] 7: 6017317 (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 May 29, 2016 May 1, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.2347G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Val783Ile missense NM_001322003.2:c.1942G>A NP_001308932.1:p.Val648Ile missense NM_001322004.2:c.1942G>A NP_001308933.1:p.Val648Ile missense NM_001322005.2:c.1942G>A NP_001308934.1:p.Val648Ile missense NM_001322006.2:c.2191G>A NP_001308935.1:p.Val731Ile missense NM_001322007.2:c.2029G>A NP_001308936.1:p.Val677Ile missense NM_001322008.2:c.2029G>A NP_001308937.1:p.Val677Ile missense NM_001322009.2:c.1975G>A NP_001308938.1:p.Val659Ile missense NM_001322010.2:c.1786G>A NP_001308939.1:p.Val596Ile missense NM_001322011.2:c.1414G>A NP_001308940.1:p.Val472Ile missense NM_001322012.2:c.1414G>A NP_001308941.1:p.Val472Ile missense NM_001322013.2:c.1774G>A NP_001308942.1:p.Val592Ile missense NM_001322014.2:c.2380G>A NP_001308943.1:p.Val794Ile missense NM_001322015.2:c.2038G>A NP_001308944.1:p.Val680Ile missense NR_136154.1:n.2391G>A non-coding transcript variant NC_000007.14:g.5977686C>T NC_000007.13:g.6017317C>T NG_008466.1:g.36421G>A LRG_161:g.36421G>A LRG_161t1:c.2347G>A - Protein change
- V783I, V596I, V648I, V680I, V472I, V659I, V731I, V592I, V677I, V794I
- Other names
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- Canonical SPDI
- NC_000007.14:5977685:C:T
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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May 12, 2022 | RCV000165312.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 1, 2023 | RCV000230774.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV000222502.11 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2023 | RCV000662655.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 29, 2022 | RCV000767022.5 | |
Likely benign (1) |
no assertion criteria provided
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- | RCV001354621.2 |
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
(Mar 01, 2021)
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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: SCV001363168.2
First in ClinVar: Jun 22, 2020 Last updated: Mar 19, 2021 |
Comment:
Variant summary: PMS2 c.2347G>A (p.Val783Ile) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. … (more)
Variant summary: PMS2 c.2347G>A (p.Val783Ile) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250156 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (5.6e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.2347G>A has been reported in the literature in an individual being tested for Lynch Syndrome (Yurgelun_2015). The report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one co-occurrence with another pathogenic variant has been reported (BRCA2 c.7008-2A>G; Yurgelun_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 02, 2016)
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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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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601843.2
First in ClinVar: May 29, 2016 Last updated: Jan 01, 2022 |
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Likely benign
(Sep 29, 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: SCV000216034.7
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
(Jul 07, 2017)
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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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Counsyl
Accession: SCV000785342.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Sep 29, 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: SCV000279208.10
First in ClinVar: May 02, 2019 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22949387, 27863258, Fukui2011[Chapter], … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22949387, 27863258, Fukui2011[Chapter], 33471991, 25980754) (less)
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Uncertain significance
(May 12, 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: SCV004359007.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with isoleucine at codon 783 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces valine with isoleucine at codon 783 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has been identified in 14/250156 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
(Dec 01, 2023)
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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: SCV000285117.6
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 783 of the PMS2 protein (p.Val783Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 783 of the PMS2 protein (p.Val783Ile). 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 missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 185820). 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 not expected to disrupt PMS2 protein function with a negative 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
(May 28, 2019)
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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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Mendelics
Accession: SCV001137279.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Dec 17, 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: SCV002530295.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PMS2 c.2347G>A (p.V783I) variant has been reported in heterozygosity in at least 1 individual who underwent Lynch syndrome testing (PMID: 25980754). It has been … (more)
The PMS2 c.2347G>A (p.V783I) variant has been reported in heterozygosity in at least 1 individual who underwent Lynch syndrome testing (PMID: 25980754). It has been reported in a large case-control study of breast cancer in 1/60466 cases and 0/53461 controls (PMID: 33471991). It was observed in 6/30514 chromosomes of the South Asian (SAS) subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 185820). In silico tools suggest the impact of the variant on protein function is benign, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Apr 04, 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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Myriad Genetics, Inc.
Accession: SCV004019824.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Feb 06, 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: SCV002550683.6
First in ClinVar: Jul 27, 2022 Last updated: Feb 14, 2024 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome
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: SCV001549282.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PMS2 p.Val783Ile variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with a history of a Lynch syndrome-related … (more)
The PMS2 p.Val783Ile variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun_2015_25980754). The variant was also identified in dbSNP (ID: rs553286217) “With Uncertain significance allele”, ClinVar (classified likely benign by Ambry Genetics and uncertain significance by GeneDx, Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x), and was not identified in the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 16 of 275380 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23840 chromosomes (freq: 0.00004), European Non-Finnish in 8 of 125530 chromosomes (freq: 0.00006), East Asian in 1 of 18756 chromosomes (freq: 0.00005), and South Asian in 6 of 30682 chromosomes (freq: 0.0002); it was not observed in the “Other”, Latino, Ashkenazi Jewish, or European Finnish populations. The variant was identified in our laboratory in 1 individual with ovarian cancer, co-occurring with a pathogenic BRCA2 variant (c.4631delA, p.Asn1544fsX24) increasing the likelihood this variant does not have clinical significance. The variant was also identified as a somatic mutation in a MSI-H/ MSH6 deficient CRC of a proband carrying a pathogenic germline MSH6 variant (c.3939_3957dup19 (p.Arg1318fs)) (Nowak_2017_ 27863258). The p.Val783 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Ile impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be 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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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 |
Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing. | Nowak JA | The Journal of molecular diagnostics : JMD | 2017 | PMID: 27863258 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. | Thompson BA | Human mutation | 2013 | PMID: 22949387 |
Text-mined citations for rs553286217 ...
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.