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NM_000535.7(PMS2):c.1420G>T (p.Ala474Ser)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(2);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Nov 3, 2021)
Last evaluated:
Sep 9, 2021
Accession:
VCV000135937.12
Variation ID:
135937
Description:
single nucleotide variant
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NM_000535.7(PMS2):c.1420G>T (p.Ala474Ser)

Allele ID
139649
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
7p22.1
Genomic location
7: 5987345 (GRCh38) GRCh38 UCSC
7: 6026976 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000007.14:g.5987345C>A
NG_008466.1:g.26762G>T
NM_000535.7:c.1420G>T MANE Select NP_000526.2:p.Ala474Ser missense
... more HGVS
Protein change
A474S, A287S, A163S, A283S, A339S, A368S, A371S, A422S
Other names
-
Canonical SPDI
NC_000007.14:5987344:C:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00002
Links
ClinGen: CA009651
dbSNP: rs373114291
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely benign 1 criteria provided, single submitter Dec 4, 2020 RCV000123078.10
Uncertain significance 1 criteria provided, single submitter Jul 12, 2021 RCV000479914.2
Uncertain significance 1 criteria provided, single submitter Sep 9, 2021 RCV001775084.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Dec 9, 2020 RCV000131575.7
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
PMS2 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
3083 3148

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely benign
(Jun 27, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000186583.6
Submitted: (Nov 30, 2020)
Evidence details
Comment:
Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
Likely benign
(Dec 04, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000166373.10
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Dec 09, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000686125.4
Submitted: (Jun 11, 2021)
Evidence details
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)
Uncertain significance
(Jul 12, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000565404.4
Submitted: (Sep 25, 2021)
Evidence details
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with a history … (more)
Uncertain significance
(Sep 09, 2021)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal cancer type 4
Allele origin: germline
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital
Accession: SCV002012391.1
Submitted: (Nov 03, 2021)
Evidence details
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)

Functional evidence

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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 this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532

Text-mined citations for rs373114291...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 11, 2021