ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.1420G>T (p.Ala474Ser)
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(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.1420G>T (p.Ala474Ser)
Variation ID: 135937 Accession: VCV000135937.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5987345 (GRCh38) [ NCBI UCSC ] 7: 6026976 (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 Apr 29, 2017 Sep 16, 2024 Feb 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.1420G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Ala474Ser missense NM_001322003.2:c.1015G>T NP_001308932.1:p.Ala339Ser missense NM_001322004.2:c.1015G>T NP_001308933.1:p.Ala339Ser missense NM_001322005.2:c.1015G>T NP_001308934.1:p.Ala339Ser missense NM_001322006.2:c.1264G>T NP_001308935.1:p.Ala422Ser missense NM_001322007.2:c.1102G>T NP_001308936.1:p.Ala368Ser missense NM_001322008.2:c.1102G>T NP_001308937.1:p.Ala368Ser missense NM_001322009.2:c.1015G>T NP_001308938.1:p.Ala339Ser missense NM_001322010.2:c.859G>T NP_001308939.1:p.Ala287Ser missense NM_001322011.2:c.487G>T NP_001308940.1:p.Ala163Ser missense NM_001322012.2:c.487G>T NP_001308941.1:p.Ala163Ser missense NM_001322013.2:c.847G>T NP_001308942.1:p.Ala283Ser missense NM_001322014.2:c.1420G>T NP_001308943.1:p.Ala474Ser missense NM_001322015.2:c.1111G>T NP_001308944.1:p.Ala371Ser missense NR_136154.1:n.1507G>T non-coding transcript variant NC_000007.14:g.5987345C>A NC_000007.13:g.6026976C>A NG_008466.1:g.26762G>T LRG_161:g.26762G>T LRG_161t1:c.1420G>T - Protein change
- A474S, A287S, A163S, A283S, A339S, A368S, A371S, A422S
- Other names
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- Canonical SPDI
- NC_000007.14:5987344:C: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 |
5240 | 5342 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Likely benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV000123078.15 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 26, 2023 | RCV000131575.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2024 | RCV000479914.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 9, 2021 | RCV001775084.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2021 | RCV003149840.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 20, 2022 | RCV001824617.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003997415.2 |
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
(Jan 20, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074367.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: PMS2 c.1420G>T (p.Ala474Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: PMS2 c.1420G>T (p.Ala474Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1420G>T has been reported in the literature in individuals affected with Lynch Syndrome, Breast cancer or Osteosarcoma as well as in healthy controls (Yurgelun_2015, Zhang_2015, Blount_2018, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Jun 27, 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: SCV000186583.8
First in ClinVar: Aug 06, 2014 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
(Feb 08, 2024)
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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: SCV000565404.8
First in ClinVar: Apr 29, 2017 Last updated: Sep 16, 2024 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a history of a Lynch syndrome-associated tumor and/or … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a history of a Lynch syndrome-associated tumor and/or polyps, breast cancer, and other cancers (PMID: 29286535, 33471991, 25980754, 26580448); This variant is associated with the following publications: (PMID: 25980754, 26580448, 29286535, 33471991) (less)
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Uncertain significance
(Sep 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002012391.2
First in ClinVar: Nov 11, 2021 Last updated: Dec 24, 2022 |
Comment:
The PMS2 c.1420G>T (p.Ala474Ser) missense change has a maximum subpopulation frequency of 0.0053% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-6026976-C-A). This variant is located in exon 11 of … (more)
The PMS2 c.1420G>T (p.Ala474Ser) missense change has a maximum subpopulation frequency of 0.0053% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-6026976-C-A). This variant is located in exon 11 of the PMS2 gene and data in this region are not considered reliable due to high pseudogene homology. This variant has been reported in an individual with a history of Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in an individual with a breast cancer and a family history of breast and other cancers (PMID: 29286535). Five of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. Due to high pseudogene homology in this region, variant confirmation by an orthogonal method (e.g. long range PCR) is recommended. (less)
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Uncertain significance
(Jun 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003837736.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Uncertain significance
(Jul 11, 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: SCV004218953.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, the variant has been reported in an individual with osteosarcoma (PMID: 26580448 (2015)), individuals with breast cancer (PMID: 33471991 (2021); LOVD3 … (more)
In the published literature, the variant has been reported in an individual with osteosarcoma (PMID: 26580448 (2015)), individuals with breast cancer (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)), and in unaffected individuals (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000053 (6/113768 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jan 26, 2023)
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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: SCV000686125.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with serine at codon 474 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with serine at codon 474 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 performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), breast cancer (PMID: 29286535, 33471991), as well as in healthy control individuals (PMID: 33471991). This variant has also been identified in 6/251492 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
(Jul 20, 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: SCV002529793.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PMS2 c.1420G>T (p.A474S) variant has been reported in individuals with Lynch syndrome-associated cancer and/or colorectal polyps, breast cancer, and osteosarcoma (PMID: 25980754, 29286535, 26580448). … (more)
The PMS2 c.1420G>T (p.A474S) variant has been reported in individuals with Lynch syndrome-associated cancer and/or colorectal polyps, breast cancer, and osteosarcoma (PMID: 25980754, 29286535, 26580448). It was observed in 6/113768 chromosomes of the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 135937). Computational analyses and evolutionary conservation data do not provide strong support for or against an impact to the protein, however these predictions have not been confirmed by published 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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Likely benign
(Feb 01, 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: SCV000166373.12
First in ClinVar: Jun 16, 2014 Last updated: Feb 14, 2024 |
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Uncertain Significance
(Feb 05, 2024)
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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: SCV004844222.1
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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Comment:
This missense variant replaces alanine with serine at codon 474 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with serine at codon 474 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 performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), breast cancer (PMID: 29286535, 33471991), osteosarcoma (PMID: 26580448), as well as in healthy control individuals (PMID: 33471991). This variant has also been identified in 6/251492 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)
Number of individuals with the variant: 11
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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 |
The changing landscape of Lynch syndrome due to PMS2 mutations. | Blount J | Clinical genetics | 2018 | PMID: 29286535 |
Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Text-mined citations for rs373114291 ...
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.